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

P.1 Description and composition of the drug product

The submission should include a detailed description of the drug product and its composition, including the dosage form in which it is to be sold in Canada, the strengths, appearance, type of container and closure system, proposed storage conditions, and expiration period.

Description of the dosage form

The description of the dosage form should include the physical description, available strengths, release mechanism, as well as any other distinguishable characteristics.

Composition

A list of all components used in the manufacturing process and incorporated in the final dosage form (e.g. pH adjusters), and their amount on a per unit basis., including overages (if any), the function of the components, and a reference to their quality standards (e.g. USP, Ph. Eur., House). The composition should express the quantity of each component on a per unit basis (e.g. mg per tablet, mg per millilitre (mL), mg per vial) and percentage basis (e.g. calculated based on the tablet core (if a non-functional coating is applied) or capsule fill weight), including the total weight or measure of the dosage unit.

The basis for the declaration of the strength should be evident in the summary of the composition of the drug product. If the strength is based on a form of the drug substance that is different from the form used in the formulation (e.g. if the drug product is formulated using a salt or solvate and the strength is declared in terms of the active moiety), then the conversion to the active ingredient should be clearly indicated (e.g. "1.075 mg active ingredient hydrochloride = 1 mg of active ingredient base").

Intra- and extra-granular excipients should be listed separately in tabular form. The qualitative and quantitative composition should be provided for all components or blends (e.g. capsule shells, colouring blends, imprinting inks, flavours). Reference to a MF can be provided for the proprietary quantitative composition; however, the qualitative composition should be included in the submission.

The function of each component (e.g. diluent/filler, binder, disintegrant, lubricant, glidant, granulating solvent, coating agent, antimicrobial preservative) should be specified. Where an excipient could have multiple functions, the most critical function should be identified. If the most critical function is not declared, scientific data should be provided to show how the excipient functions in the formulation and evidence that the excipient is not functioning in a more critical fashion. For example, Microcrystalline Cellulose should be assessed as a binder not a filler unless data is provided to support that its primary function is not as a binder and that other binders are present. If a multifunctional excipient is used and the variation between strengths is greater than what is allowed by HC's policy on "Bioequivalence of proportional formulations: Solid oral dosage forms", then justification should be provided for the proposed variation (e.g. granule size distribution, tablet hardness, dissolution).

Adjustment of a filler at the drug substance dispensing stage to account for as-is-assay of the drug substance is acceptable and should be clearly documented.

Where applicable, the following should also be provided:

Description of accompanying reconstitution diluent(s). For drug products supplied with reconstitution diluents, chemistry and manufacturing information on the diluents should be provided separately as a subsection under the appropriate drug product section.
The type and description for the CCS for the dosage form (and accompanying reconstitution diluent, if applicable) should be brief with further details provided under P.7 Packaging (e.g. "The product is available in HDPE bottles with polypropylene caps and in PVC/Aluminum foil unit dose blisters").
Description of accompanying dosing devices. If the product is to be administered using a device such as a dosing spoon, syringe, dropper, etc., a brief description of the device should be provided with further details provided under section P.7.

P.2 Pharmaceutical development

The pharmaceutical development section of the submission should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, CCS, microbiological attributes, and usage instructions, as appropriate for the purpose specified in the submission.

The studies to be described in this section are distinguished from routine control tests conducted according to drug product specifications. Additionally, the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance, and drug product quality should be described. Supportive data and results from specific studies or published literature can be included within or attached as a narrative to this section. Additional supportive data can be cross-referenced to the relevant sections as needed.

The pharmaceutical development section should include elements defining the quality target product profile (QTPP) of the drug product as it relates to quality, safety and efficacy.

Typical quality attributes and process parameters vary for different dosage forms. Some attributes could be critical and should be established by the company on a case-by-case basis depending on the complexity of the dosage form and manufacturing process presented by the product.

Storage and usage information – In-use periods

The usage instructions found in the Storage section of the Package Insert need to be supported by acceptable data (e.g. in-use periods, maximum number of punctures, compatibility with listed administration media/diluents, uniformity of split scored tablets, dispersion in liquid, use of a feeding tube, storage of admixtures).

P.2.1 Components of the drug product

P.2.1.1 Drug substance

The discussion of the physicochemical characteristics of the drug substance should include the possible influence of the drug substance solubility, particle size, crystal form, or any other characteristic on the performance of the drug product.

For drug products that are a combination of multiple drug substances, the compatibility of the drug substances with each other should be discussed. The compatibility of the drug substance with excipients used in the formulation should be discussed.

Critical quality attributes (CQAs) of the drug substance that can impact manufacturability should also be identified (e.g. particle size distribution). Additionally, CQAs of the drug substance that can be affected by manufacturing conditions and consequently have an impact on the drug product CQAs should be identified (e.g. assay and impurities CQAs due to sensitivity of the drug substance to light, heat, moisture or environment).

In-situ conversion

A drug substance may be converted to a different chemical or physical form (e.g. in- situ conversion of free base to salt, change of stereoisomer or polymorphic form) during the drug product manufacturing process. Such a conversion could be intended or inadvertent (e.g. processing condition in commercial lot). Nevertheless, such a conversion may adversely affect the performance, safety and efficacy of the drug product. Instances where there is a potential for in-situ conversion based on the physicochemical properties of the drug substance or due to the formulation and/or method of manufacture of the drug product, justification and supporting data should be provided to establish whether a conversion occurs, leading to a different physical or chemical form of the drug substance contained in the final dosage form.

Where investigation of the drug product shows that the physical (e.g. polymorphic, pseudo-polymorphic or particle size distribution) or chemical (e.g. free acid/base to salt) form of the drug substance is altered during the manufacturing process or during storage of the drug product, section P.5 should include relevant information (e.g. solubility, crystalline structure) for the drug substance and as much information as possible regarding the in-situ chemical form contained in the finished drug product. In order to make a risk-based decision on the acceptability of the in-situ transformation, information on the in-situ form should include information on the salt form if it were present as an isolated compound (e.g. solubility). Where complete characterization of the original or in-situ form is not possible, this should be discussed. Published literature could also be presented as supporting information/data to justify the presence or absence of in-situ conversion.

In a generic product, if an in-situ conversion occurs to a form of the drug substance which is different from that in the CRP, additional information should be submitted to support the safety and efficacy of the form of the drug substance in the final dosage form.

P.2.1.2 Excipients

The choice of excipients, their concentration, and their characteristics that can influence the drug product performance should be discussed relative to their respective functions. Detailed information should be provided to identify the excipients (e.g. grades, potato vs. corn starch, excipients with multiple origins such as magnesium stearate). The potential CQAs of the excipients including the selection of their type/grade and amount, and their effect on the delivery of the drug product of the desired quality should be discussed and justified. When compendial monographs allow for different acceptance criteria for tests for different grades of excipients, the selection of the appropriate grade should be discussed. It may be necessary to control an excipient using tighter limits if the monograph is not suitable to control the critical properties for the excipients (e.g. viscosity of a rate controlling excipient).

As absorption modifiers (e.g. enhancers, inhibitors) and aids such as surfactants could significantly influence bioavailability, their use should be justified. Use of novel excipients or excipients at levels higher than routinely used should be supported by documented evidence of their safety for use in animals. None of the excipients which are in the drug product should be on the list of prohibited colouring agents listed in the Canadian Food and Drugs Act and Regulations.

Micro tracers in drug premixes

Micro tracers typically consist of iron or stainless steel particles colored with food dyes. When formulated in a medicated premix, micro tracers allow the manufacturer to identify the premix and the medicated feed containing it as proprietary. The presence and detection of the micro tracer also facilitates the validation of mixing studies and the adequacy of batch to batch cleanout.

Information concerning a micro tracer used in a medicated premix should include:

a full description of the micro tracer and its composition
specifications and test methods for the tracer
analytical data to demonstrate that the presence of the micro tracer does not interfere with the assay of the medicinal ingredient in the premix and the medicated feed, and
stability data for the drug premix and medicated feed(s) containing the micro tracer (see section P.8 Stability – Drug premixes)

P.2.2 Drug product

P.2.2.1 Formulation development

The drug product formulation and manufacturing process proposed for marketing in Canada should be the same as those used in development (i.e. pivotal clinical or bioavailability studies). Any differences in the formulations for the batches used in the pivotal clinical or comparative bioavailability and the formulation (i.e. composition) described in section P.1 should be included and supported by appropriate bridging studies. Results from comparative in vitro studies (e.g. dissolution, physicochemical properties) or comparative in vivo studies (e.g. bioequivalence) should be discussed, when appropriate.

When assessing the data elements needed for multiple strengths or variations in composition between the batches used in the comparative bioavailability and the commercial formulation, HC's policy on "Bioequivalence of proportional formulations: Solid oral dosage forms" should be consulted. If a request for waiver of bioequivalence studies is proposed, the allowed variations in formulation should comply with this policy. In general, careful assessment of excipient roles would be made based on their concentration alone.

Where antioxidants are included in the formulation, the effectiveness of the proposed concentration of the antioxidant should be justified and verified by appropriate studies.

Where an antimicrobial preservative is included in the formulation, the effectiveness of the agent should be demonstrated using a batch of the drug product with the preservative concentration at the lower limit of the proposed acceptance criteria for the assay. Schedule B compendial tests for antimicrobial effectiveness testing are considered acceptable. References to the results from microbiological attribute testing provided under section P.2.5 can be made as appropriate. The use of antimicrobial preservatives in single-dose preparations is not recommended.

P.2.2.2 Overages

Any overages in the formulation(s) described in the submission should be justified. Overage for the sole purpose of extending the shelf life of the drug product is not acceptable; however, if the overage is required to make up for a validated loss during the manufacturing process (e.g. loss during vacuum transfer) or to fill void space (e.g. excess coating solution to fill the tubing) it should be presented along with justification and supporting data for its necessity and quantity.

P.2.2.3 Physicochemical and biological properties

Parameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties, biological activity or potency, and/or immunological activity, should be addressed.

For a generic product, evidence from the comparative physiochemical studies conducted in connection with the submission that the proposed drug is pharmaceutically equivalent to the CRP should be submitted. For more information on the key physiochemical properties of different dosage forms, refer to Table 4 (Relevant physiochemical properties of different dosage forms) outlined in HC's "Preparation of Veterinary Abbreviated and New Drug Submissions (Generic Drugs) – Clinical and Human Safety Requirements".

A summary of the dissolution development should also be included in this section. For recommendations when conducting comparative dissolution profiles, refer to Appendix 1. Recommendations for conducting and assessing comparative dissolution profiles in Post-Notice of Compliance (NOC) Changes: Guidance for quality of veterinary drugs.

Scored tablets

Tablet score design should be confirmed by tests. The results of a study should be provided testing the uniformity of dosage units of the tablet and the tablet should be split as described in the package insert (e.g. split by hand or split with a device such as a tablet splitter). The data provided in the drug submission should include a description of the test method, individual values, mean, and relative standard deviation (RSD). Uniformity testing (i.e. content uniformity or weight variation, depending on the dose present in the split tablet) should be performed on each split portion from a minimum of 15 randomly selected whole tablets.

Loss of mass from the tablets during splitting should be documented and should not exceed 3.0%. At least one batch of each strength should be tested. The study should cover a range of hardness values. If this study is not done during development, then the acceptability of the hardness range should be confirmed during process validation by including a tablet splitting study on high and low hardness tablets in the process validation protocol. The uniformity test on split portions can be demonstrated on a one-time basis and does not need to be added to the drug product specification(s). The acceptance criteria (range and variation) should be as described in the general chapters of the pharmacopoeia (e.g. USP General Chapter <905>, Ph. Eur. 2.9.40).

In order to allow a score line on a modified release tablet the formulation design has to be suitable (e.g. tablet should not disintegrate) and splitting the tablet should not compromise drug release from the split halves (i.e. meets the predetermined release profile). For modified release products with a score line, in addition to content uniformity, equivalent rates of release should be demonstrated for the split tablets vs. whole tablets.

If present, the tablet description on the drug product specifications, and the labelling, should reflect the presence of a score. If immediate or modified release products cannot be split or the splitting of the tablets is not listed in the directions on the labelling, a score line should not be present.

For a generic product, additional information should be provided with respect to its design such as geometry of the scored tablet, break-line, similarity with the CRP, and choice of manufacturing process (e.g. hardness that would be conducive to splitting the tablet).

P.2.3 Manufacturing process development

A brief summary describing the development of the drug product should be provided, taking into account the proposed route of administration and usage. The choice of higher risk manufacturing process (e.g. aseptic processing instead of terminal sterilization, direct compression instead of granulation) should be justified. All CQAs and the CPPs should be identified, and explained. A control strategy should be proposed to ensure the batches meet the predetermined specification.

Differences between the manufacturing process(es) used to produce the bio-lots and the process described in section P.3.3 that can influence the performance of the drug product should be discussed.

In accordance with C.08.002.1(2)(d) of the FDR, the information provided in the submission should provide evidence that all test batches of the new drug used in any studies conducted in connection with the submission were manufactured and controlled in a manner that is representative of market production.

This section should briefly document any changes to the manufacturing process throughout the life cycle of the drug product covered by the submission. A side-by-side table comparing the manufacturing process of the product used for pivotal studies to the product currently proposed (e.g. the proposed commercial process or the revised process proposed in a SNDS or ANDS) is recommended. A discussion of the significance of the differences should be included as well as any data supporting the proposed changes (e.g. in-vitro testing or biostudies).

A side-by-side table comparing the manufacturing process of the product used in the bioequivalence studies to the product currently proposed (e.g. the proposed commercial process or the revised process proposed in an SNDS or (S)ANDS) is recommended. A discussion of the significance of the differences should be included as well as any data supporting the proposed changes (e.g. in-vitro testing or biostudies).

A scientific rationale using the principles of risk management should be provided for the choice of the manufacturing, filling, packaging processes, and storage conditions that can affect the quality and performance of the drug product. Appropriate controls of the CQAs and CPPs should be established to ensure the process consistently manufactures the drug product. If applicable, developmental work should be discussed to establish appropriate controls to avoid deterioration of the drug substance during manufacturing process and storage (e.g. protection from heat, light (UV or visible), oxygen or moisture).

Where proven acceptable ranges (PARs)have been claimed in section P.3.3, studies which support the proposed ranges should be described. Studies conducted to assess criticality of process parameters or material attributes identified in P.3.4 should also be described.

If environmental controls over and above routine controls are necessary to ensure the stability of the drug product during the manufacturing process, the additional controls such as reduced lighting or a different lighting source, temperature and humidity control, or use of an inert atmosphere should be discussed and rationalized in the submission.

For sterile drug products, results of studies should be provided demonstrating compatibility (e.g. hold time studies, extractables and leachables data, risk assessment of elemental impurities) with manufacturing equipment (e.g. coated vessels, sterilization filters, transfer tubing).

Drug product intermediate

The first processing step of the drug substance in the presence of any other substance would be considered a drug product manufacturing activity, subject to Part C, Division 2 of the FDR, and would define the date from which the expiry date for the drug product would be established.

Mixtures of two drug substances are considered a drug product intermediate and the date of manufacture would be considered the date that the two drug substances are first mixed. If the drug product intermediate is not used immediately and an expiry date or retest date is set for the drug product intermediate, then the stability data to support the shelf life (expiry date) of the finished dosage form should be based on data from batches of drug product which have been manufactured using the drug product intermediate just before its proposed expiry date.

Under certain circumstances for which an alternative to the above interpretation may apply – such as the inability to isolate the drug substance in a pure and stable form, or mixing with excipients for safety or stability purposes (e.g. nitroglycerin) - sponsors are advised to consult VDD at vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca to discuss their case and scientific justification in advance.

Scale-up during manufacturing process development

The scientific rationale for the selection, optimization, and scale-up of the manufacturing process described in P.3.3 should be explained, in particular the CPP that are linked to CQAs of the drug product (e.g. the rate of addition of granulating fluid, massing time, granulation end point, drying end point, and in process control range for the LOD which determine the quality of the granules). The critical equipment required for ensuring product quality should be identified (e.g. model and item number) by operating principles and working capacity.

The rationale for selection of manufacturing processes should be fully outlined and the suitability of the selected manufacturing process and control strategy should be demonstrated on at least one commercial size lot of each strength. This lot would serve as a proof of concept, to demonstrate scalability and commercialization. The production of a commercial scale batch is recommended for all products, especially high-risk products as outlined below:

When the drug substance is a critical dose drug and the drug product is not a solution
When the drug product strength is 5 mg or lower and/or the drug substance forms 2% (w/w) or less of the total mass of the drug product content, or
When the chosen manufacturing process is:
1. prone to variability (e.g. direct compression process for manufacturing a low dose product), or
2. complex (e.g. use of coating technology to add the drug substance and/or a rate controlling function to granules, processes which include lyophilisation or microencapsulation)

Sterile drug products

For sterile drug products, terminal sterilization is considered to be the method of choice to ensure sterility of the final drug product. As a result, sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible. Manufacturers who choose to manufacture a sterile product without terminal sterilization (e.g. aseptic processing) should provide adequate scientific justification and supporting data for the proposed sterilization technique. Evidence should be provided to confirm that the sterilization process will produce a sterile product with a high degree of reliability and that the physical and chemical properties as well as the safety of the drug product will not be affected. Details such as F₀ range, temperature range and peak dwell time for a drug product and the CCS should be provided. Justification should be provided for reduced temperature cycles or elevated temperature cycles with shortened exposure times. A rationale is not required for standard autoclaving cycles of 121°C for 15 minutes or more.

If ethylene oxide is used, acceptance criteria should be included in specifications to control the levels of residual ethylene oxide and related compounds.

The suitability of filters selected for sterilization should be established by studies evaluating bacterial retention and viability, compatibility with the product during the maximum contact time, extractables and leachables, and adsorption of the drug substance or any of the formulation components. If applicable, the description and the data for a validated flush program should be submitted to demonstrate that the filter is suitable for the filtration process.

The suitability and compatibility of the manufacturing equipment (e.g. extractables and leachables) should be demonstrated for non-solid dosage forms. Minimum product rinse volumes should be established.

Drug premixes

Drug premixes cannot be administered directly to animals and are formulated for blending into animal feed prior to administration. As such, additional testing is required to evaluate the quality of the medicated feed. To ensure compatibility and homogeneity of the medicated feed, results from the mixing study conducted during pharmaceutical development should be provided.

Homogeneity studies

Due to the very low content of the drug substance in animal feeds, proper mixing is essential in the manufacturing of medicated feeds to ensure uniform dispersion of the drug substance in the final feed - evidence should be provided to demonstrate this. The composition of the final feed used for the studies should be clearly stated and be representative of the feed used for the intended target species. To demonstrate homogeneity of the medicated feed, sufficient samples should be taken from three (3) pilot/registration batches and evaluated for assay from various points in the blender (i.e. top, middle, and bottom of the mix) following the usual mixing cycle. The size of the samples should take into consideration the daily intake of the target species. In addition to assay data, a discussion on the particle size, electrostatic properties, type of mixing machinery, and mixing in stages or trituration should be included. Specific mixing instructions should be included in the directions for use in the products labels based on the results from the mixing studies.

Segregation studies

As medicated feeds are frequently transported over long distances, unless otherwise justified, evidence should be provided to demonstrate that no segregation of the drug substance is observed from the medicated feed during transportation and to affirm no loss of homogeneity.

P.2.4 Container closure system

The suitability of the CCS (described in P.7) used for storage, transportation (shipping) and use of the drug product should be established. This should include the choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form, including absorption to container and leaching, safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).

The information that should be included for the qualification of the CCS includes packaging material(s) that:

come in direct contact with the dosage form (container, closure, liner, desiccant)
are used as a protective barrier to help ensure stability or sterility
are used for drug delivery
are necessary to ensure drug product quality during transportation

The following table outlines parameters which should be used to establish the suitability of the CCS.

Table P.2.4-1: Parameters to establish the suitability of the CCS
Parameter	Oral and topical products	Inhalation products	Sterile products (including ophthalmics)
Name, physical description, dimensions (e.g. thickness, volume, diameter)	✓	✓	✓
Specific identification tests (e.g. IR) for components that come in direct contact with the dosage form	✓	✓	✓
Tests for reproducibility of dose delivery (or packaging materials responsible for delivery of a dose)	✓ (if applicable)	✓	✓ (if applicable)
Composition and drawings for all novel or product specific components (including cap liners, coatings for metal tubes, elastomers, adhesives, silicone, etc.)	✓	✓	✓
Description of any additional treatments ^{Footnote 1}	✓	✓	✓ (sterilization and depyrogenation of the components)
USP <661> Plastic Packaging Systems and their materials of construction (Includes 661.1 and 661.2)	✓	✓	✓ (includes USP <87> / <88> / <1031> tests)
USP <671> Containers–- Performance Testing	✓	✓	✓
USP <381> Elastomeric Closures for Injections	--	--	✓ ^{Footnote 4} (includes USP <87> / <88> tests)
Additional tests	^{Footnote 2}	^{Footnote 2}	^{Footnote 2}
Compatibility with drug product (e.g. adsorption to the container and related substances)	✓ (Liquid oral products and liquid or semi-solid topical products)	✓	✓
Extractable and Leachable studies	✓ (Liquid oral products)^{Footnote 3}	✓ ^{Footnote 3}	✓ ^{Footnote 3}
✓ information should be submitted -- information does not need to be submitted
Footnote 1 Treatments can include coating of tubes, siliconization of rubber stoppers, sulphur treatment of ampoules/vials, blanketing with inert gas. Return to footnote 1 referrer Footnote 2 refer to the guidance document Pharmaceutical quality of aqueous solutions for details of additional tests required (e.g. extractables and leachables, performance tests for metered dose drug delivery). Return to footnote 2 referrer Footnote 3 refer to the USP <1663> and <1664> / <1664.1> for guidance on extractables and leachables testing. This information can be provided in a master file, if relevant. Return to footnote 3 referrer Footnote 4 For multi-dose injectables, the conditions used for the functionality tests (e.g. needle gauge size, number of punctures) should be adapted to align with the conditions established as worst-case scenario during in-use period stability studies. Return to footnote 4 referrer

The information on the composition of packaging used for parenteral and liquid/semi-solid products should be made available either in the drug submission or in a MF. For more information on MFs, refer to "Guidance on procedures and administrative requirements for master files".

P.2.5 Microbiological attributes

Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products (see VICH GL39) and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives, or the anti-microbial effectiveness of products that are inherently antimicrobial. For sterile products, the integrity of the CCS to prevent microbial contamination should be addressed (i.e. USP <1207>).

As outlined in VICH GL3, for verification purposes, a single primary stability batch of the drug product should be tested for antimicrobial preservative effectiveness, in addition to preservative content, at the proposed shelf life regardless of whether there is a difference between the release and shelf life acceptance criteria for preservative content. If this information is not available at the time of submission, a commitment should be provided that a single primary stability batch will be tested for antimicrobial effectiveness at the end of proposed shelf life.

P.2.6 Compatibility

For reconstituted products, the compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g. precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labels. Data from constitution or dilution studies that are performed as part of the formal stability studies to confirm product quality through shelf life should be provided under section P.8.3.

Where sterile, reconstituted products are to be further diluted, compatibility should be demonstrated with all diluents over the range of dilution concentrations proposed in the labels. The results from the studies performed should bracket the listed concentrations. These studies should be conducted on aged samples; refer to section P.2 for more guidance on in-use periods. Where the labelling does not specify the type of containers, compatibility with respect to parameters such as appearance, pH, assay, levels of individual and total degradation products, sub-visible particulate matter, and extractables from the packaging components should be demonstrated in the specified container(s) (e.g. glass, PVC, and polyolefin containers). If one or more containers are identified in the labelling, compatibility of admixtures needs to be demonstrated in the specified containers.

Studies should cover the duration of storage reported in the labelling (e.g. 24 hours under controlled room temperature and 72 hours under refrigeration).

When qualifying limits for degradation product, the maximum level observed for impurities should be considered in the reconstituted product at the end of the in-use period. For generic products, if levels of impurities or other parameters warrant, reconstitution studies should be carried out in parallel with the CRP to adequately qualify the impurity and other limits proposed in the drug product specification(s).

Known or potential incompatibilities (e.g. lactose with drug substance containing primary amine) should also be discussed and the controls to minimize the effect of these potential incompatibilities should be identified (e.g. control of impurities, physical separation via manufacturing techniques).

Drug premixes proposed for concurrent use

For drug premixes recommended for concurrent use, compatibility data should be provided to demonstrate that the drug substances are chemically compatible (i.e. no drug-drug interactions and degradations are present) and stable throughout the shelf life under the recommended storage conditions of the medicated feed. Critical factors that may affect the identity and strength of the final medicated feed must be identified and controlled. The analytical method used for assay determination of each drug substance should retain its accuracy and precision in the presence of the other drug substances. If the other drug substances interfere in the analysis, a new analytical method will be required. For concurrent use of drugs in liquid feeds, a discussion on the drug-drug interactions and degradations should be provided.

The following information should be submitted for combination in dry/liquid feeds:

Data to demonstrate non-interference of the feed assay analytical method. Cross-reference could be made to the approved submission or published literature. If a new analytical method is required, analytical validation report should be submitted.
Mixing studies on three (3) production scale batches to demonstrate homogeneity and no segregation of the medicated feed mixture.
Stability data of the medicated feed mixture (requirements are as described under P.8). The shelf life and storage conditions of the medicated feed mixture should be established.

For dry feeds, cross reference could be made to the approved submission for the individual premix with a rationale that the addition of a small amount of another premix is not likely to impact homogeneity and stability of the feed mixture. As the probability of drug interaction and degradation is high in a liquid matrix, cross-reference to an approved data or published literature is not acceptable for liquid feeds.

P.3 Manufacture

If an MF is filed with HC and cross-referenced for certain proprietary information, provide the MF number assigned by HC.

P.3.1 Manufacturer(s)

Manufacturing activities must meet GMP requirements of Division 2, Part C of the FDR. The submission should include the name, address, and responsibility of all sites, including those contracted and involved in licensable activities such as manufacturing, packaging, labelling, testing (release and stability), importing, storage, and distribution of the drug product. Companies performing only specific steps in the process (e.g. manufacturing of an intermediate) should be indicated. Sites involved in sterilization of primary CCSs (e.g. gamma radiation) not subsequently exposed to terminal sterilization should be listed. The address provided should be for the site where the activity takes place rather than the administrative offices. The manufacturing, packaging, labelling, and testing facilities should be confirmed by HC's ROEB to be GMP compliant. It is recommended that confirmation of GMP compliance is determined prior to submitting an application.

P.3.2 Batch formula

The submission should include the batch formula in tabular form for each proposed batch size, indicating the amount of each component on a per-batch basis and the corresponding quality standard (e.g. USP, Ph. Eur., House, etc.). The batch formula should include all components used in the manufacturing process regardless of whether the component appears in the final drug product (e.g. solvents, nitrogen, etc.). If the amount of drug substance added to the batch formula does not correspond to the label claim (e.g. drug substance added as a salt while label claim is expressed as the base), the appropriate conversion factors should be indicated as a footnote to the table. If there is a granulation step using intra- and extra-granular excipients, these should be listed separately.

The batch formula should be written to provide 100% of the label claim unless overages have been adequately justified. All overages should be clearly indicated (e.g. "Contains 5 kg overage of the drug substance to compensate for manufacturing losses."). An overage of film-coating suspension can be justified in a footnote to the batch formula table.

P.3.3 Description of manufacturing process and process controls

Flow diagram

The submission should include a flow diagram showing each step of the process and where materials enter. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified.

Narrative description

The submission should include a narrative summary of the manufacturing process, including packaging and labelling describing the sequence of steps, as well as the scale of equipment, where relevant. The summary should be based on the details listed in the Master Production Documents (MPDs) for the proposed commercial batch size. The amount of ingredient added at each step, the equipment type and capacity, process parameters such as mixing times and speeds, processing temperatures, and any precautions necessary to ensure product quality, such as control of humidity, temperature, light, and maximum hold times, where necessary should be provided. Associated numeric values can be presented as an expected range. Numeric ranges for critical steps should be justified. In certain cases, environmental conditions (e.g. low humidity for an effervescent product) should be stated.

In-process testing

The in-process testing should be indicated, and it is recommended that the testing be presented in tabular form, including the process step, test conducted, and acceptance criteria. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Equipment should, at least, be identified by type (e.g. tumble blender, in-line homogenizer) and working capacity, where relevant.

Critical process parameters

Specific process parameters (e.g. mixing speed, granulation end point) should be included and should correspond with the target and normal operating ranges (NORs) included in the MPDs for commercial scale batches. If data to support a design space is provided in section P.3.3, then the proposed design space should be clearly described - a tabular summary of process parameters and design space is a recommended format for presenting this information. Where PARs for discrete process parameters have been supported by data in section P.2.3, the manufacturing process should be described in terms of targets and NORs identified in the master batch records. A combination of PARs does not constitute a design space and it is expected that the manufacturing process will be conducted within the NORs for all process parameters.

Manufacturing process times

Validated maximum manufacturing process times, including hold times, should be included as specified in the MPDs. Unless clearly stated and authorized, the start of manufacturing for the purposes of establishing the drug product shelf life is defined as the date of the first processing step of the drug substance in the presence of any other substance used in the manufacture of the drug product.

Unless data is available to support longer manufacturing process times, the time from start of manufacture to the end of manufacture should not be more than 30 days. The time of final manufacture to the end of packaging in the final CCS should not be more than 60 days for solid drug products. Unless data is available to support longer manufacturing process times, the time from the start of manufacturing to the end of packaging in the final CCS (i.e. end of sealing including the sterilization procedures or start of the lyophilization process, if applicable) should not be more than 24 hours for liquid drug products.

Reprocessing

Proposals for the reprocessing of materials should be justified and the data to support this justification should be either referenced or filed in this section. Reprocessing of materials is not expected in a validated process and will only be considered in exceptional circumstances (e.g. recirculation of fines) -if it is to be done on a routine basis, then this should be submitted as part of the manufacturing process with relevant supporting data. The acceptability of such reprocessing of materials is determined on a case-by-case basis based on the data showing control of the drug product.

Sterile products

For sterile drug products, details of validated sterilization parameters (e.g. load size, autoclave program, gamma radiation dose, processing aids) and equipment (e.g. compounding vessels, sterilizing filters, filling syringes) should be listed for the drug product and all relevant stages of the manufacturing process (e.g. for the washing, sterilization and depyrogenation of packaging components). The sterilization cycle should be described where contract manufacturers are used for sterilization of packaging components, or alternatively this information could be provided in a MF (i.e. Type II Container Closure System Master Files).

As outlined in the general chapters of the pharmacopoeia, each container of an injectable drug product should be filled with a volume that slightly exceeds the content indicated in the product labelling. These excess volumes are known as overfills, not to be confused with overages, and are intended to ensure the minimum required extractable volumes to allow for correct dosage delivery. The master manufacturing documents should include target fills and tolerance limits to ensure that at least 100% of the label claim of the drug substance will be available. Overfills that exceed the recommended excess volume in general chapters of the pharmacopoeias (e.g. USP <1151>) should be justified and supported by data.

P.3.4 Controls of critical steps and intermediates

Tests and acceptance criteria should be provided with justification, including experimental data, and should be performed at the critical steps identified in P.3.3 of the manufacturing process to ensure that the process is controlled. Information on the quality and control of intermediates during the process should be provided (e.g. co-precipitates, bulk tablets and solutions).

In-process tests are performed during manufacturing for the purpose of adjusting process parameters within an operating range to ensure the entire batch meets the expected quality attributes. Hence, in-process test limits may be used as action limits. For tablet compression, the quality attributes tested in-process could include weight, hardness, disintegration time, and friability. All routine in-process controls should be listed in this section, whether critical or not. If an in-process control is not critical, it is acceptable to state that it is just monitored. All process parameters (critical and non-critical) are managed under the product quality change management system. The sponsor manages critical parameter ranges as regulatory commitments and any changes in the critical ranges would be provided for regulatory assessment in compliance with the current "Post-Notice of Compliance (NOC) Changes: Guidance for quality of veterinary drugs" document. In the rare case where a non-CPP range is changed and the resulting change is determined to impact a drug product CQAs, the non-CCP would be re-designated as a CPP and the VDD would be notified following current post-NOC regulatory guidelines. In-process controls monitored during process validation only should be described under section P.3.5. Sampling frequency and acceptance criteria should also be listed, and a tabular format is recommended.

Examples of potential in-process controls include:

Granulations: moisture, blend uniformity, bulk and tapped densities, granule particle size distribution, granulation end point
Solid oral products: average weight, weight variation, hardness, thickness, friability, disintegration, weight gain during coating
Semi-solids: viscosity, homogeneity, pH, evaluation of phase separation
Transdermal patches: assay of drug-adhesive mixture, weight per area of coated patch without backing, adhesion strength, cut patch dimensions and tolerances
Metered dose inhalers: fill weight/volume, leak testing, valve delivery, crimp dimensions and leak testing for pressurized products
Liquids: pH, specific gravity, clarity of solutions, bioburden
Implants: average weight, weight variation, hardness, thickness, friability, disintegration, weight gain during coating, moisture, blend uniformity, bulk and tapped densities, particle size distribution, pH, specific gravity, clarity of solutions
Parenterals: bioburden prior to sterilization, 100% visual inspection (appearance, clarity), pH, fill volume/weight, filter integrity tests (determined pre and post filtration using appropriate methods (e.g. bubble point or forward flow)), particulate matter, container closure integrity test

Weight variation in-process controls

The generally accepted standard for in-process limits for weight variation for the core tablets and hard capsule fill weight, for a product with a robust process using a modern tablet press and encapsulation equipment, is considered to be ± 3-5% for average tablet weight and ± 5% for individual tablet weight. A less stringent limit is acceptable in exceptional cases where it is difficult to achieve a tighter control. Justification with data is required if wider limits are proposed (e.g. a dosage form that presents challenges in manufacturing, very small tablets, bilayer tablets). The strength of the medicinal ingredient(s) in a tablet or capsule is affected by the weight of the tablet or capsule; therefore, acceptability of weight variation limits beyond the individual and average limits are determined on a case-by-case basis. Controls for packaging should be provided when they are critical for ensuring appropriate quality (e.g. leak testing and controls for orientation of vials, or bottles for sterile products).

P.3.5 Process validation and/or evaluation

Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g. validation of the sterilization process or aseptic processing or filling). Viral safety evaluation should be provided, if necessary.

Prospective process validation studies should be conducted on three (3) consecutive commercial scale batches of the drug product prior to the distribution of the drug product. This is a pre-planned scientific approach and includes the initial stages of formulation development, process development, setting of process specifications, developing in-process tests, sampling plans, designing of batch records, defining raw material specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size batches, listing major process equipment, and environmental controls. Traditional process validation is generally performed prospectively, using three consecutive commercial size batches. Continuous Process Verification (CPV) could be applied to drug products developed with Quality by Design (QbD) principles (ICH Q8). Documentation should include the process validation report (if available) and the validation protocol. Alternatively, a commitment can be provided to complete process validation studies prior to commercialization. Concurrent validation would be acceptable under certain conditions with prior approval (e.g. low volume drug products).

The following information should be provided for prospective process validation:

The process validation protocol or validation report (for three (3) consecutive commercial scale batches) specific to the drug product, which identifies the critical equipment and CPPs that can affect the CQAs of the drug product and defines testing parameters, sampling plans, analytical procedures, and acceptance criteria (Control Strategy)
Confirmation that three (3) consecutive, production-scale batches of the drug product have been or will be subjected to prospective validation in accordance with HC's guidance document "Guide to Validation – Drugs and Supporting activities (GUI-0029)". Alternative approaches to prospective validation should be accompanied by a detailed justification.

Non-sterile products

The submission should include the process validation protocol, specific to the drug product and should:

identify the critical steps, equipment, and process parameters that can affect the quality of the drug product
define testing parameters, sampling plans, analytical procedures and acceptance criteria
confirm that three (3) consecutive production scale batches will be subjected to validation

If process validation studies have already been completed, the submission should include the process validation report.

Sterile products

For sterile products, validation of the sterilization process should be completed, and data should be provided in the submission. Documentation should include the process validation protocol and reports on the validation studies.

Terminal sterilization

Terminal sterilization, when practical, is considered to be the method of choice to ensure sterility of the drug product. If any other method of sterilization is selected, the submission should include scientific justification for the selection. For terminal sterilization, the manufacturing process should be validated according to HC's guidance document "Process validation: Moist Heat Sterilization for Pharmaceuticals".

Aseptic processing

For sterile products which undergo aseptic processing, the manufacturing process should be validated according to HC's guidance document "Process validation: Aseptic processes for pharmaceuticals." The results of the three (3) consecutive media fills (i.e. aseptic process simulation study) which is sufficiently representative of the proposed commercial manufacturing process should be provided (e.g. with respect to the process type, batch size, container/closure configuration, container size, volume to be filled per unit, filling speed, process duration, number of units filled, etc.). Scientific justification should be provided for any differences between the media fill process parameters and those proposed for the commercial process.

The submission should also provide documentation on the following:

Process parameters of the sterilization cycle
Bacterial retention capacity, solution compatibility and leachables, as well as filter integrity
Washing, treatment, sterilizing, and depyrogenating containers, closures, and equipment
Bioburden prior to sterilization (NMT 10 CFU/100 mL)
Filtration of solutions
Filter integrity tests (prior and post filtration using appropriate methods (e.g. bubble point or forward flow)
The lyophilization cycle
The type and number of sterilizing filters, filter area, material and nominal pore size;
Information on holding times for each step of processing (between start of compounding and filtration, after filtration (if bulk solution is held) and prior to filling, as well as total filtration and filling time)
The integrity test of filled and sealed container closures
Final inspection of the product (e.g. 100% inspection for visual particulates as per USP<790> Visible Particulates in Injections)

P.4 Control of excipients

P.4.1 Specifications

The submission should include specifications for all excipients, including processing aids that do not appear in the drug product (e.g. solvents, nitrogen, silicone for stoppers, etc.).

If the excipient complies with a Schedule B compendial monograph, it is acceptable for the submission to simply state that the excipient will be tested according to that standard. If the excipient is non-compendial or is compendial with additional tests or tighter limits, the submission should include the specification. If a manufacturer's standard is claimed, testing should be at least, as specified in the Schedule B compendial monograph, should one or more exist. If a compendial standard is claimed, the standard only has to meet the requirements of the appropriate monograph. Excipients derived from natural sources should have appropriate microbial tests and limits.

For excipients which are mixtures that are provided by third party manufacturers such as flavours, colourants, and non-functional coatings, a qualitative list of the ingredients should be provided along with their specifications. Additional proprietary information on each excipient, if applicable, should be provided in an MF (e.g. quantitative composition, grades of materials used during manufacturing).

Functional excipient

Characteristics that are recognized as being relevant control parameters for one or more functions of the excipient should be appropriately controlled and details provided. If developmental studies show that a particular characteristic is critical for the functionality (e.g. viscosity or particle size of release controlling excipients), it should be included in the specifications. For novel excipients, information should be provided in section P.4.6, or cross-referenced to the MF number which includes this complete information.

P.4.2 Analytical procedures

The submission should include analytical procedures, where appropriate, for tests supplementary to those listed in a Schedule B compendial monograph, as well as for all tests in specifications for non-compendial excipients. Analytical procedures from Schedule B compendial monographs do not need to be submitted.

P.4.3 Validation of analytical procedures

Validation reports for commonly used test methods (e.g. compendial methods, particle size testing by laser diffraction) for excipients are normally not submitted, however the reports should be available on-site and provided to HC on request.

P.4.4 Justification of specifications

The submission should include justification for tests and acceptance criteria supplementary to those appearing in a Schedule B compendial monograph, as well as for all tests in specifications for non-compendial excipients.

P.4.5 Excipients of animal origin

For excipients of animal origin, the submission should include information concerning adventitious agents, including sources, specifications, descriptions of the test(s) performed, and viral safety data. This information should include biological source, country of origin, manufacturer, production methods, and a brief description of the suitability of its use based on the proposed controls.

For excipients manufactured from raw material obtained from sources that have potential of transmitting BSE/TSE agents (e.g. ruminant origin), a letter of attestation, with information on production methods used to ensure TSE inactivation, should be provided attesting that the excipient is not at risk of transmitting BSE/TSE. A current certificate of suitability provided by EDQM may be used as an attestation. Alternatively, information supporting the safety of the source from the proposed supplier should be provided (e.g. in a MF registered with HC).

P.4.6 Novel excipients

A decision as to whether an excipient is novel is based on prior usage of the excipient in products marketed in Canada. For excipient(s) used for the first time in a drug product or by a new route of administration, the submission should include full details of the manufacture and characterization of the novel excipient. The submission should also include cross references to any supporting clinical safety data. For novel excipients, information should be provided in the submission or cross-referenced to the MF number which includes this complete information. For novel excipients where a large amount of information is submitted, a high-level summary of that information should be provided. A summary of toxicological information submitted to support a novel excipient or daily exposure of an excipient should be listed here. If the excipient has been used in products marketed in other jurisdictions, this information can be submitted as a supporting justification for its use.

P.5 Control of drug product

P.5.1 Specification(s)

The submission should include the specification(s) for the drug product. The concept of "release and shelf life specifications" vs. "regulatory acceptance criteria" is described in VICH GL39 - either approach would be considered acceptable. Tighter release acceptance criteria for assay should be proposed in order to ensure that shelf life acceptance criteria are met throughout the labelled shelf life of the drug product. For example, release assay limits of 93.0-108.0% label claim would generally be acceptable when the shelf life assay limits are 90.0-110.0% and degradation product levels increase by less than 2.0% over the shelf life.

The drug product specifications in accordance with C.02.018 and C.02.019 of the FDR should be provided from the site responsible for release (e.g. drug product manufacturer, importer or distributor). 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, and date for version control purposes. The standard declared by the sponsor could be a FDA, Schedule B compendial standard, manufacturer's standard, prescribed standard (e.g. Canadian Standard Drugs in Division 6 of the FDR), or a professed standard.

Although a Schedule B compendial monograph may exist, a sponsor can choose to declare a manufacturer's standard. However, the specifications must at minimum meet the pharmacopeial standard.

For a drug where no Schedule B compendial standard exists, a professed standard is used and the product labelling for such products does not carry any standard claim.

Tests for product appearance, identity (by specific tests such as IR, HPLC-UV) and assay of the medicinal ingredients and determination of degradation products are standard for all dosage forms. The other tests to be included in the specification will depend on the dosage form and route of administration. 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). The chemical names of each specified impurity should be defined as a footnote to the table if ambiguous designations such as abbreviations and/or company codes are used. Dissolution method parameters (e.g. dissolution apparatus, rotation speed, dissolution medium and volume) should be listed as a footnote to the table or directly in the description of the test.

For a generic product, the proposed limits for degradation products that exceed the VICH qualifications threshold of 1.0% can be qualified by comparison with the CRP as discussed in section P.5.5 "Impurities".

All products are expected to meet the minimum requirements for microbial control in accordance with the relevant general chapters of the pharmacopoeias (e.g. USP <1111>). For certain veterinary products, such as solid oral dosage forms, justification can be provided to omit testing from the specifications for routine product release testing as recommended in VICH GL39. Finished products are also expected to meet residual solvents requirements as per VICH GL18.

If specifications are different for powders and their reconstituted solutions, this information should be clearly identified.

An outline of the recommended tests and acceptance criteria considered generally applicable to all new medicinal products are outlined in VICH GL39 and in the applicable Ph. Eur. and USP general chapters (e.g. product quality tests, performance tests). Table P.5.1-1 provides additional recommended specific tests.

Table P.5.1-1: Additional recommended specific test parameters ^{Footnote a},^{Footnote b}not covered in VICH GL39 and in relevant USP general chapters
Dosage form	Tests
Transdermal (i.e. patches)	Mean weight per unit area
Aerosols	Spray pattern
Semi-solids products (pastes, gels, creams, ointments)"	Dose delivery and weight variation Syringeability
Suppositories	Melting point
Premixes	Moisture content Particle size/sieve analysis
Teat dips/udder washes	pH Specific gravity Viscosity Microbial testing
Injectable implants	Diameter, length Hardness, friability Release rate/dissolution Microbial testing
Footnote a Where applicable. Return to footnote a referrer Footnote b Where applicable tests are more appropriate as developmental tests these should be provided under section P.2 Pharmaceutical Development and justification for not including them as routine tests should be provided under section P.5. Return to footnote b referrer

P.5.2 Analytical procedures

The submission should contain the analytical procedures proposed for testing the drug product. It is not necessary to provide Schedule B compendial analytical procedures unless the procedures are modified.

All house analytical procedures proposed for routine testing should be provided. Summaries of the methods used for the drug development or differences between these methods and routine quality control methods (e.g. those used to support testing results in the drug submission) should be provided.

Chromatographic analytical procedures (i.e. chromatographic conditions) should include system suitability testing (SST). For HPLC/UPLC and GC procedures, the SST should include as a minimum, resolution and repeatability (minimum five replicates), but may also include tests such as number of theoretical plates and tailing factor. Repeatability is typically demonstrated using a solution of the drug substance with a concentration corresponding to the limit for unspecified degradation products. Resolution of the two closest eluting peaks is generally recommended as an SST. However, choice of alternate peaks (e.g. choice of a toxic impurity) or another appropriate test to determine column performance could be used with justification. For TLC procedures, confirmation of sensitivity and component separation as an SST may be acceptable.

P.5.3 Validation of analytical procedures

The submission should include the validation reports for the analytical procedures proposed for testing the drug product. The reports should include the protocol used, the results obtained for each validation characteristic, interpretation and discussion of the results, and conclusions reached. The choice of characteristics to be validated should be consistent with the type of analytical procedure and intended purpose.

For compendial methods, confirmation should be provided to state that verification of compendial procedures as per the relevant general chapters of the pharmacopoeias (e.g. USP <1226>) has been completed successfully in compliance with the requirements outlined in the relevant compendium. Partial re-validation may be necessary for methods from Schedule B compendial monographs as the composition of the product used for validation of the compendial procedures is likely to be different from the proposed product. Different sources of the same drug substance or drug product can contain impurities and degradation products that were not considered during the development of the monograph.

If a house procedure is used in lieu of a compendial procedure for assay or determination of degradation products, the house procedure should be fully validated and its equivalency to the compendial procedure should be demonstrated. This could be accomplished by performing analyses of a batch containing significant levels of impurities by both methods and providing the results from the study.

Drug premixes

Details of the validated analytical methods used for identification and assay determination of the drug substance in the medicated feed should be provided.

If a drug is to be administered as a medicated feed, an acceptable method of analysis for the drug, when mixed in typical complete feeds at the recommended level, should be provided. The submission should include the following information:

A clear and concise description of the methodology, including a description of the drug, feed type (e.g. mash, pellets), and type of analytical techniques for each drug of interest
Method performance standards (i.e., recoveries, analytical ranges, limits of quantification and detection, and coefficients of variation for repeatability)
Critical control points
Experimental designs and statistical plans
Raw data, chromatograms, tracings, calculated results, statistical results, and quality control for methods
Interference studies and documentation. If the product is a mixture, the different drug components that the method can determine should be described
Stability-indicating test parameters
Familiarization procedures for new analysts
Other related documentation such as ruggedness studies, confirmatory and trace level procedures, collaborative studies, and references

P.5.4 Batch analyses

A description of batches and results of batch analyses should be provided. It is expected that drug product lots used in bioequivalence studies and those submitted in the submission (e.g. to establish specifications for potency, purity, dissolution and shelf life) are manufactured and tested according to GMP principles in order to ensure the reliability of the analytical test results. Deviations and OOS test results should be investigated in a timely manner and the results of the investigation summarized in the submission. Justifications with supporting data where necessary should be provided to support the use of the identified lots for setting regulatory specifications for release and stability.

A tabulated summary of batches discussed in the submission to support safety, efficacy, product development, process validation and stability should be provided in the QOS and should include the batch number, strength, manufacturing site, manufacturing process, testing site, batch size, date of manufacture, drug substance batch number, and use of the batch. Batches used in pivotal clinical or bioequivalence studies should be clearly indicated. If any batches have multiple batch numbers (e.g. different batch numbering systems or manufacturing batch numbers different from packaging batch numbers) the table should incorporate this information so all batches and their uses can be properly identified.

Number of batches and batch sizes

It is expected that a minimum of three (3) batches of each strength should be manufactured at a minimum of pilot scale from each proposed commercial manufacturing site, and that complete analytical results should be provided for those batches.

For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger. For liquid dosage forms (including lyophilized powders for reconstitution into a solution), a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 20 liters, whichever is the larger. If the maximum proposed commercial batch size is less than 20 liters, the executed batches included in the drug submission should be manufactured at the maximum proposed commercial batch size.

In addition, batch analyses should be provided for batches used in pivotal clinical or bioequivalence studies and batches used for qualification of impurities. Bracketing or matrixing can be applied (e.g. if formulations are a common blend) and if scientifically justified by comparative data and understanding of the process. If matrixing is applied, then batch analyses for a minimum of one batch of each strength should be provided, ensuring that batches are provided from a minimum of two batches of common blend.

CoA for pivotal batch(es) should be provided. If CoAs for the release testing of three (3) executed batches of each strength are not provided in the submission, the complete information from the certificates should be provided in tabular format. Tabulated summaries in the QOS should be sufficiently detailed and include the date of manufacture of the batch, and date and site of testing. Quantitative results should be provided for all tests conducted, and the range, mean, and relative standard deviation of individual results should be provided for content uniformity and dissolution. The RRT 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, should be provided as well as the LOD where applicable (e.g. when impurities are not detected). Results of additional tests may be provided here or in section P.5.6 to justify omission of certain tests from the specification.

P.5.5 Characterization of impurities

Information on the characterization of impurities should be provided, if not previously provided in "S.3.2 Impurities". This information should include, if applicable, degradation products (e.g. from interaction of the drug substance with excipients or the CCS) and solvents in the manufacturing process for the drug product.

P.5.6 Justification of specification(s)

The justification of the specification should 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. A full elemental impurities risk assessment should be conducted demonstrating compliance with Ph. Eur. General Monograph 2619. The justification of specifications should be based on the recommendations described in VICH GL39, GL11, GL18, GL51 and other relevant guidance documents.

In vitro dissolution or drug release

A dissolution test is an important performance indicating test for oral dosage forms (e.g. tablets, capsules, oral suspensions) and non-oral dosage forms (e.g. transdermal, suppositories, premixes), and is often used to link changes in the product at various stages of its lifecycle. Its utility as an important test to make key decisions depends on how relevant the test is to product performance and whether it has any discriminatory power.

Dissolution results should be submitted for all relevant executed batches, including those lots used for pharmacokinetic and bioavailability studies (pivotal clinical lots). Results from pivotal clinical lots should be used as the basis for setting the specification and providing a link to the product's QTPP. Instances where the clinical (pivotal) lot has expired (e.g. to justify a post-NOC change), a more recent commercial lot that represents the pivotal lot could be used instead as the reference if concurrent testing is required. This should be supported by a justification that the reference lot meets the QTTP. Any differences in the formulation and/or manufacturing process should also be explained and evidence provided that the changes have not affected the dissolution performance.

The results of studies justifying the choice of in vitro dissolution or drug release conditions (i.e. apparatus, rotation speed, medium) should be provided. Data should also be submitted to demonstrate whether the method is sensitive to changes in manufacturing processes and/or changes in grades and/or amounts of critical excipients. The dissolution method should be sensitive to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters. The use of dissolution parameters from a dissolution method included in a pharmacopoeial drug product monograph or from the FDA Recommended Dissolution methods should be justified and the conditions should be shown to be relevant for the drug product under assessment. The VICH GL39 Decision Tree #7 should be consulted to establish appropriate drug release acceptance criteria.

For immediate release drug products, the use of a single point test or a dissolution range should be justified based on the solubility and/or biopharmaceutical classification of the drug. For slowly dissolving or low solubility drugs, it may be necessary to test at additional time-points in order to demonstrate adequate dissolution to characterise the quality of the product. For example, if the time to achieve ≥85% exceeds 30 minutes, a two-point test should be considered. Dissolution testing and therefore dissolution drug product specifications are formulation and drug product specific tests.

For a generic product, the specifications should be representative of the release of the biolot(s), hence, it may be necessary to define acceptance criteria which are tighter than those cited within compendial monographs.

Modified-release dosage forms should have a meaningful in vitro release rate (dissolution) test that is used for routine quality control. Preferably this test should possess in vivo - in vitro correlation. Results demonstrating the effect of pH on the dissolution profile should be submitted if appropriate for the type of dosage form. Ideally, the testing conditions should be set to cover the entire time period of expected in vivo release (e.g. 12-hour release, twice a day) unless a shorter timeframe is justified (e.g. using clinical, bioequivalence, or pharmacokinetic studies).

The method development and validation should not be limited to validation of the method used for quantification (e.g. UV, HPLC/UPLC, etc.) but should include the capacity of the method to discriminate between formulation and manufacturing variables and the rationale for the choice of the type of dissolution apparatus, stirrer speed (RPM), volume and pH of the dissolution medium, etc. If a surfactant is used, both the choice of surfactant and the concentration should be justified. If a surfactant is justified, the minimum level of surfactant required to reach sink conditions should be selected. The RSD for dissolution at time points beyond the initial time point should be less than 10%. Evidence that the method is discriminatory should also be included in section P.5.3.

Transdermal patch adhesion

Adhesion of the patch should be tested to assess the patch's adhesive property (also termed a peel test or shear test). It is a numerical value obtained from an in vitro test and is useful to detect any manufacturing anomaly and serves as an index to monitor stability. The in vitro method for testing patch adhesion generally has little correlation with its adhesion property on the animals. As a result, the proposed patch adhesion numbers in the specification should be linked to the adhesion observed in clinical studies.

P.6 Reference standards or materials

Information on the reference standards or reference materials used for testing of the drug product should be provided, if not previously provided in section S.5.

P.7 Container closure system

For requirements on the container closure system, refer to section S.6 for more information.

A description and specifications should be provided for the packaging components that:

come in direct contact with the dosage form (container, closure (e.g. rubber stoppers), liner, desiccant)
are used as a protective barrier to help ensure stability or sterility (e.g. nitrogen headspace)
are used for drug delivery (e.g. syringe, dropper, measuring cup)
are necessary to ensure drug product quality during transportation

If a MF is filed with HC and cross-referenced for certain proprietary information (e.g. composition), provide the MF number assigned by Health Canada. If processing agents (e.g. silicone for stoppers) are applied by the vendor, then they should be listed in this section. Include all proposed market containers and containers used for bulk storage. The information for the CCS depends on the dosage form and route of administration. The following table outlines the general recommendations for routine testing for various dosage forms.

Table P.7-1: Testing that should be included routinely in the container closure system component specifications for various dosage forms
Specifications for routine testing:	Oral and topical	Inhalation	Sterile products (including ophthalmic)
Name, physical description, dimensions (e.g. thickness)	✓	✓	✓
Specific identification tests (e.g. IR) for components that come in direct contact with the dosage form or are primary packaging components	✓	✓	✓
Performance characteristics necessary for product delivery	✓ (if applicable)	✓	✓
Extractable and Leachable ^{Footnote 1}	✓ (if warranted)	✓	✓
Footnote 1 Refer to USP <1664> for guidance on risk-based approach for consideration. Return to footnote 1 referrer

Results of extractable/leachable studies should be provided for components in contact with aqueous solutions. The tests should investigate the aqueous (and other applicable solvents) extraction of the plastic to characterize or determine the presence of impurities or extractables. If possible, the extraction media should also include the drug vehicle to be used. Testing should meet the requirements of the USP General Chapters <87/88> Biological Reactivity. Additional results from extraction and/or leachable studies may be warranted depending on the characteristics of the drug product and the primary components of the CCS (e.g. risk of glass delamination).

Certificates of compliance, if relevant, can be provided from either the vendor or drug product manufacturer.

P.8 Stability

Stability testing results should be provided to determine how the quality of the drug product varies with time under the influence of environmental factors such as temperature, humidity, and light. The recommended storage conditions and shelf life should be established based on these studies. Information on the analytical procedures used to generate the data and validation of these procedures should be included.

Photostability testing should be conducted on at least one (1) primary batch of the drug product, if appropriate. The standard conditions for photostability testing are described in VICH GL5.

The results from the stress studies conducted should show degradation of the drug product to demonstrate that the analytical procedures used for the purity and potency tests are stability-indicating with mass-balance (i.e. process of adding together the assay value and levels of degradation products to add up closely to 100%) observed. Representative chromatograms of stress studies showing 10-20% degradation of the active drug substance should be submitted.

Additional stress testing of certain types of dosage forms may be appropriate (e.g. cyclic freeze-thaw studies for liquids, orientation of the CCS (such as inverted), semi-solids, and transdermal patches).

Drug premixes

Stability studies should be conducted to support the proposed shelf life for the medicated feed. Other stability studies in relation to conditioning and pelleting, segregation and homogeneity may also be required.

The studies should be conducted using production scale batches of the medicated feed. Pilot scales (at least 10% of production scale of the medicated feed and usually at least 50 kg) may be used to generate relevant data in cases where the production scale of the medicated feed may not be available during product development.

Stability data should be provided for the drug premix after incorporation in a typical feed, for the intended species, following the preparation instructions, as described in the product labels, to support the proposed shelf life of the medicated feed. The choice of feed used in the study should consider that feeds contain additives, vitamins, minerals, trace elements, binders, and preservatives. A list of substances with known chemical incompatibilities with the drug substance should be included.

The type, nature, and quality of the feed in which the premix will be incorporated should be clearly described in the labels. The levels of incorporation of the premix in the animal feed should be stated and a description should be provided to describe how the premix is incorporated into the animal feed.

At a minimum, three (3) months stability testing results from at least three (3) batches of medicated feed at the recommended level as mash or pellets, prepared from at least two different batches of the medicated premix, should be provided at 25°C ± 2°C / 60% ± 5% RH (long-term testing) and at 40°C ± 2°C / 75% ± 5% RH (accelerated testing). The information on the stability studies should include details such as storage conditions, strength, batch number, batch size, date of manufacture, type of CCS, and completed test intervals. Assay is typically the only test required. Testing should be carried out initially and then at one-month intervals. If the premix is to be incorporated into the feed at various concentrations, stability studies should be done at both the lowest and highest levels recommended. Shelf life should be established based on the stability of the medicated feed. The storage conditions and shelf life of the medicated feed should be stated on the product labels, including any specific instructions for incorporation of the premix into the animal feed.

The composition, type and quality of the animal feed (e.g. mash, crumbs, pellets) used in the study should be clearly described. In cases where there are differences in the composition of the feed for one category or age of animal, or if the product is intended for more than one species, stability studies conducted with different animal feeds may be required. For medicated feeds supplied as both mash and pellets, stability studies should be conducted on both types. If a range of incorporation rates is proposed, then stability studies should be carried out at the highest and lowest levels of this range.

Data on the feed assays before and after pelletizing to determine the effects of pelletizing should be provided. Post-pelletization assays should be repeated at monthly intervals up to three months. If it is expected that pellet-binding agents will be used, then the three-month study should include at least one feed pelletized with and without the binding agents at the recommended use level.

The testing should be carried out in the final packaging proposed for marketing. The use of smaller comparable containers simulating the actual market packaging may be justified.

P.8.1 Stability summary and conclusion

Conclusions with respect to storage conditions and shelf life and, if applicable, in-use storage conditions and in-use period should be given.

Accelerated and long-term studies

The submission should include a stability study protocol indicating the selection of batches, storage conditions, frequency of testing, CCS, tests and acceptance criteria, as recommended in VICH GL3.

Results should be provided for a minimum of three (3) batches of each strength in each proposed container/closure system. Two of the three batches should be at least pilot scale batches. Bracketing and matrixing can be applied if scientifically justified. For example, if the drug product has a common blend and compressed to different tablet weights (strengths), then a minimum of one lot of each strength should be placed on stability. The following storage conditions and minimum data at the time of submission are recommended by VICH GL3. For drug products intended for storage in a refrigerator or freezer, other study conditions per VICH GL3 may be required.

Table P.8.1-1: General case for stability studies of the drug product
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	6 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. The initial application should include a minimum of 6 months of data from a 12-month study at the intermediate storage condition.

The information on the stability studies should include details such as storage conditions, strength, batch number, batch size, date of manufacture, type of CCS, orientation for liquid dosage forms (e.g. upright, inverted), and completed and proposed test intervals. Data should be summarized in tabular format for all batches/strengths/CCSs which exhibit similar stability profiles. This should include ranges of analytical results and/or relevant results for justifying the proposed shelf life (e.g. maximum values for each time-point if an increasing trend is observed for impurities).

The actual stability results (i.e. raw data) used to support the proposed shelf life should be provided and tabulated by batch and time-point.

All impurities observed above the reporting threshold should be reported and identified by name if known, or by retention time, or applicable code if unknown.

If there is more than one packaging format, such as blisters and bottles, then each format should be studied. Analytical procedures that differ from those described in section P.5.2 should be included along with appropriate validation data.

The discussion of results should focus on observations noted for the various tests, rather than reporting comments such as "All tests meet specifications". Any trends that were observed or statistical analysis performed should be discussed.

All studies should report appearance, assay, and degradation products, while the other tests to be conducted will depend on the dosage form and route of administration. Some tests, such as sterility, particulate matter, and bacterial endotoxins, need not be performed at every test interval.

For drug products that require reconstitution or dilution, the submission should supply stability results to support the proposed storage periods of the reconstituted or diluted product. When the drug product contains preservative to prevent oxidation or microbial activity, the submission should include an assay for preservative content at time zero and at the end of the proposed shelf life to ensure quality and performance of the drug product up to the end of the shelf life. Where the antimicrobial preservative lower assay limit is less than 90%, preservative effectiveness studies at the proposed lower limit for preservative content should be conducted.

Proposed storage conditions and shelf life

The submission should include the proposed storage conditions with suitable tolerances (e.g. a temperature range with upper and lower criteria) and the shelf life of the drug product in each commercial container/closure system based on the results of the stability studies. If more than one packaging format is available, and with different storage conditions and/or shelf life, the CCS should be included.

When the drug product has been shown to be stable (e.g. under the VICH conditions with long term studies at 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" on the label would generally be considered acceptable. If any adverse trends are observed, different storage recommendations may be warranted (e.g. "Store at 15°C to 25°C").

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. Open-ended storage conditions such as "Store below 30 °C" should not be used unless stability data have been provided to demonstrate stability under refrigerated and frozen conditions. Stability data from studies conducted at temperatures below 15°C should be included for drug products which may be susceptible to precipitation or low temperature induced changes (e.g. solutions, suspensions and solid dispersions). Terms such as "ambient conditions" or "room temperature" should be avoided.

Based on the assessment of the stability data, other storage precautions should be assessed, and precautionary statements added to the label if warranted (e.g. "Protect from light", "Protect from moisture", "Store in the overwrap provided"). Precautionary statements should not be a substitute for selecting the appropriate CCS.

If justified, at the time of the application for market authorization, the real time data generated under long-term storage conditions can be extrapolated according to VICH GL51 to extend the in-use period.

In-use stability studies

The testing to support the in-use period should be performed at the end of the in-use period on a batch near the end of the proposed shelf life for the drug product provided. If data is not available at the time of filing, data based on an in-use period study performed at an earlier date and projected stability at the shelf life and a commitment to reconfirm the studies at the end of the shelf life should be provided unless stability data clearly supports that no significant degradation is expected. The testing should be performed in such a way that the use of the drug product mimics consumer use (e.g. the final remaining amount of the product is tested after opening and closing the bottle and removing product) as listed in the Package Insert.

The in-use period statement should be established for products in multi-dose containers after first opening. The quality parameters of the drug product susceptible to change should be evaluated over the proposed in-use period. In-use periods should be justified with data where applicable and consistent with product labelling (e.g. for multi-dose products containing a preservative, in-use periods should be justified with experimental data). The in-use period and in-use storage conditions, if applicable, should be supported by appropriate in-use stability data to demonstrate that the drug product remains within its shelf life specifications. Data for a minimum of two (2) pilot scale batches, one of which should be approaching the end of its shelf life, should be provided.

For multi-dose injectable drugs, the in-use stability study design should consider all target species and labeled dosage(s) when determining the theoretical maximum number of punctures and needle size. The in-use period stability study design should simulate the practice of the drug product use in the field at intervals comparable to the volume of the drug product. If multiple container/closure sizes are available for a single drug product, a single in-use stability study may be used to represent more than one container size if identical elastomeric stopper formulations are used for all container/closure systems. The smallest stopper size could be considered as the worst-case scenario in this case. A justification should be provided to ensure the worst-case scenario is considered.

The design of the in-use stability testing should consider the following:

All intended species and routes of administration
The overall largest needle gauge normally used in the practice should be used. A justification should be provided if special circumstances exist
The theoretical maximum number of punctures should be used whenever possible and should be based on the intended species receiving the maximum number of doses per container. If the stopper cannot withstand the theoretical maximum number of punctures, an in-use statement restricting the maximum number of punctures or the use of multi-dose equipment, or both, may be required
Assay of the preservative should be part of the testing parameters, and the minimum preservative assay acceptance criterion should be supported by Antimicrobial Effectiveness Testing data at the lowest acceptable preservative concentration. If no chemical preservatives are used, AET testing is not required
The in-use statement on labels should be supported by the data generated from the in-use period stability study. The maximum number of punctures, in-use period, storage conditions and/or restriction statements should be included as appropriate.

P.8.2 Post-approval stability protocol and stability commitment

The post-approval stability protocol and stability commitment should be provided.

Primary batch stability

When the available long-term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, or the stability data submitted is conducted on pilot scale batches, a commitment should be made to continue the stability studies in order to firmly establish the shelf life.

Production scale batch stability

If the primary batches are not production scale, a commitment should be provided to place three (3) commercial size production scale batches of each strength into the stability program post-approval. The long-term stability studies for the commitment batches should be conducted through the proposed shelf life, and for six months under accelerated conditions.

The stability protocols for the commitment batches should include, but are not limited to:

Number of batches per strength and batch sizes
Tests and acceptance criteria
CCS(s)
Testing frequency, and
Storage conditions (and tolerances) of samples.

Bracketing and matrixing can be applied if justified. Any differences in the stability protocols used for the primary batches and those proposed for the commitment batches should be scientifically justified.

P.8.3 Stability data

A tabulated summary of the stability results, with graphical representation where appropriate, should be included. Information on the analytical procedures used to generate the data and validation of these procedures should be included.

The actual stability results (i.e. raw data) used to support the proposed shelf life should be provided and tabulated by batch and timepoint.

Data from the stress studies should be provided. This data can be referenced for validation of analytical procedures, as appropriate. Data from supporting studies can also be included, if considered appropriate.

P.9 Production documentation

P.9.1 Executed production documents

A minimum of three (3) batches including one (1) batch of each proposed strength should be manufactured with generally executed documents for one batch of each strength provided. The batches should be manufactured using a procedure fully representative of and simulating that to be applied to a full production scale batch.

For solid oral drug products, a pilot scale is generally considered, at a minimum, to be one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is larger.

The executed production documents (English or French original or translated) should be provided for the batches used in the pivotal comparative clinical or bioavailability studies with any notations on the executed production documents clearly made.

When there are more than 2 pivotal batches, executed production documentation submitted can be limited to 1 pivotal batch per strength as long as executed documents are provided for a minimum of 2 batches that cover the range of strengths. When 2 or more pivotal batches have been manufactured and a suitable matrixing/bracketing approach is proposed, a minimum of 2 pivotal executed batches per product should be provided and executed documents from a minimum of the highest and lowest strength per manufacturing site should be included. When a batch of a strength which has not been used for a pivotal study is submitted, the executed document for the primary stability batch should be submitted.

Representative documentation from each commercial manufacturing site should be provided. Bracketing or matrixing is acceptable, if scientifically justified.

P.9.2 Master production documents (MPDs)

The submission should include the drug product MPDs for each proposed strength, and commercial batch size. The details in the MPDs should include, but are not limited to, the following:

the name and batch number of the product
dates and times of commencement, of significant intermediate stages and of completion of production
dispensing, processing, and packaging sections, with relevant material and operational details
relevant calculations (e.g. if the amount of drug substance is adjusted based on the potency results or on the anhydrous basis)
identification of all equipment by type and working capacity (if applicable)
process parameters (e.g. mixing time, mixing speed, milling screen size, processing temperature range, tablet machine speed, vial filling speed, pre-compression force, main compression force, feeder speed)
list of in-process tests (e.g. appearance, pH, potency, blend uniformity, viscosity, particle size distribution, loss on drying, weight variation, hardness, disintegration time, weight gain during coating, leaker test, minimum fill, clarity, bioburden, filter integrity test, 100% visual inspection)
any deviation (e.g. out of specification results, delay in process) from the Manufacturing Formula and Processing Instructions should be described and clearly justified;
sampling plan with regard to the steps where sampling should be done (e.g. drying, lubrication, and compression)
the number of samples that should be tested (e.g. blend drawn using a sampling thief from x number of different parts of the blender)
the frequency of testing (e.g. weight variation every x minutes during compression or capsule filling)
precautions necessary to ensure product quality (e.g. temperature and humidity control, maximum holding times, total processing time)
theoretical and actual yield

Where any of this information is included in a SOP (Standard Operating Procedure), MPDs should clearly reference the SOP by name, number or code. Where documents are updated frequently, a reference to the current version of the document can be made rather than including a specific version number.

For sterile products, instructions for cleaning, sterilization, and if relevant, depyrogenation procedures for equipment and primary CCS components should be provided in the MPDs or in referenced SOPs.

If the production instructions or critical control parameters are present in SOPs, the SOP should be provided. Examples of SOPs which should be provided are:

Procedures which contain Bubble Point test parameters (acceptance criteria)
Aseptic Filtration of Bulk Solution (e.g. specification of filling speed, filters used)
Procedures for aseptic filling, stoppering, lyophilization or autoclave loading and operation parameters, unloading, sealing
Procedure for dispensing of Raw Materials (if this contains formulation information)
Procedures for operation of critical equipment (e.g. blending vessels, 100% visual testing where the Acceptable Quality Levels are listed in the SOP)

A brief summary of SOP titles listed in production documents should be provided in the submission, and if requested by the assessor, the SOP should be made available.

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2025-08-07

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

On This Page

P.1 Description and composition of the drug product

Description of the dosage form

Composition

P.2 Pharmaceutical development

P.2.1 Components of the drug product

P.2.1.1 Drug substance

P.2.1.2 Excipients

P.2.2 Drug product

P.2.2.1 Formulation development

P.2.2.2 Overages

P.2.2.3 Physicochemical and biological properties

P.2.3 Manufacturing process development

P.2.4 Container closure system

P.2.5 Microbiological attributes

P.2.6 Compatibility

P.3 Manufacture

P.3.1 Manufacturer(s)

P.3.2 Batch formula

P.3.3 Description of manufacturing process and process controls

P.3.4 Controls of critical steps and intermediates

P.3.5 Process validation and/or evaluation

P.4 Control of excipients

P.4.1 Specifications

P.4.2 Analytical procedures

P.4.3 Validation of analytical procedures

P.4.4 Justification of specifications

P.4.5 Excipients of animal origin

P.4.6 Novel excipients

P.5 Control of drug product

P.5.1 Specification(s)

P.5.2 Analytical procedures

P.5.3 Validation of analytical procedures

P.5.4 Batch analyses

P.5.5 Characterization of impurities

P.5.6 Justification of specification(s)

P.6 Reference standards or materials

P.7 Container closure system

P.8 Stability

P.8.1 Stability summary and conclusion

P.8.2 Post-approval stability protocol and stability commitment

P.8.3 Stability data

P.9 Production documentation

P.9.1 Executed production documents

P.9.2 Master production documents (MPDs)

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