Post-Notice of Compliance (NOC) Changes: Guidance for quality of veterinary drugs: Examples (drug substance)

On this page

• Introduction
• 3.2.S.1 General information
• 3.2.S.2 Manufacture
• 3.2.S.3 Characterisation
• 3.2.S.4 Control of the drug substance
• 3.2.S.6 Container closure system
• 3.2.S.7 Stability

Introduction

The change examples provided in this guidance are not considered to be exhaustive such as to cover all possible situations. When in doubt as to the classification or supporting documentation, sponsors should contact the Veterinary Drugs Directorate for clarification.

The change examples presented below are intended to assist with classifying changes made to the quality information. The information summarized in the tables provides recommendations for:

• The conditions to be fulfilled for a given change to be classified as either a Level I, II, or III change. If the conditions outlined for a given change are not fulfilled, the change is automatically considered the next higher level of change. For example:
  • if the conditions recommended for a Level II - Notifiable Change are not fulfilled, the change is considered a Level I - Supplement
  • if the conditions recommended for a Level I - Supplement are not fulfilled, the change would warrant the filing of an NDS or an ANDS
• The supporting data for a given change, either to be submitted to Health Canada and/or maintained by the sponsor. Where Master Production Documents are required, make these documents available in an official language (English or French), or a translation from the original language.
• The reporting category (such as Supplement, Notifiable Change or Annual Notification).

Health Canada reserves the right to request additional information or material as deemed appropriate, or to define conditions not specifically described in this document. Sponsors should contact the directorate when a change that may have the potential to impact product quality is not found in the tables.

Although the Common Technical Document (CTD) format is not applicable to veterinary drugs submissions, but for convenience, the change examples are organized according to the structure of the CTD.

3.2.S.1 General information

1. Change in the drug substance name/nomenclature

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the drug substance name/nomenclature	1	1,2	Annual Notification

Conditions

1. Confirmation that the information on the drug substance has not changed as a result of the change. For example, cross reference(s) should be provided to the previously approved drug submission, including:
   • brand name of the drug product
   • manufacturer or sponsor's name
   • submission type
   • control number
   • date approved

Supporting data

1. Package Insert and Inner and Outer Labels, if applicable
2. (S.1.1) Information on the proposed nomenclature of the drug substance, for example:
   • chemical name(s)
   • compendial name (Schedule B of the Food and Drug Regulations)
   • evidence that the proposed name for the drug substance is recognized, such as:
     • British Approved Names (BAN)
     • United States Adopted Names (USAN)
     • Recommended International Non-Proprietary Name (INN)

3.2.S.2 Manufacture

2. Changes to starting materials

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Replacement or addition of a manufacturing site	None	1-6	Notifiable Change
	1-4	1-6	Annual Notification
Changes to the route of synthesis (such as reagents), with or without a change in manufacturing site	None	1-6	Notifiable Change
	1-4	1-6	Annual Notification

Conditions

1. No changes to the specifications for the starting material other than addition of tests to the specifications or tightening of acceptance criteria.
2. Analytical methodology (HPLC, LC-MS-MS) has been used to survey the impurity profile of the starting material and ensure that purging of impurities from subsequent drug substance manufacturing steps has occurred.
3. The manufacturing process for the drug substance that is performed under Good Manufacturing Practices (GMP) has at least 3 synthetic steps prior to the final salt production or purification steps.
4. There is no change in the route of synthesis of the non-commercial starting material (including reagents) other than the addition of purification steps and/or changes to solvents that are VICH GL18(R) class 2 or 3. The impurity profile of the drug substance remains the same (no new impurities above the VICH GL10(R) identification threshold and no new identified impurities).

Supporting data

1. (S.2.3) Name and address of starting material manufacturer.
2. (S.2.3) Specifications for starting material.
3. (S.2.3) Route of synthesis of a non-commercially available starting material. Note: Route of synthesis would include basic information about the synthetic reactions that are used (such as a flow chart) and would include reagents and solvents but would not involve detailed information about the reaction conditions or process. For fermentation or semi-synthetic processes, it would involve a similar level of detail.
4. (S.2.3, S.4.4) Analytical data to support consistent impurity profiles between the previously authorized and new starting material, and between drug substance manufactured with the previously authorized and new starting material.
5. (S.2.5, S.2.6, S.3.2) The new source(s) of starting material (or reagents/catalysts or solvents) have been used during drug substance manufacture, validation (if applicable), and technology transfer (if applicable). For sterile drug substances, applicable process validation studies are successfully completed to manufacture commercial size batches of the drug substance. Potential impurities not routinely tested have been confirmed to be absent from the impurity profile of the drug substance by either testing, risk analysis, or knowledge of fate/purge of impurities.
6. (S.2.6) Risk assessments and justification of changes that any changes are minor or insignificant. The assessment discusses those changes that result in changes to the specifications of the starting material, related intermediate or the final drug substance. The impact assessment considers potential for any new impurities, carry-over of all impurities and whether changes to the starting material specifications are needed.

3. Changes to drug substance intermediates

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Replacement or addition of a manufacturing site	None	1-7	Notifiable Change
	1-4	1-7	Annual Notification
Changes to specifications	None	4,5	Notifiable Change
	1,2	4	Annual Notification
Changes to the manufacturing process, with or without change in manufacturing site	None	1-7	Notifiable Change
	1-4	1-7	Annual Notification

Conditions

1. A written quality agreement is in place between the intermediate manufacturer and the drug substance manufacturer.
2. No changes to the specifications for the intermediate other than addition of tests to the specifications or tightening of acceptance criteria.
3. Analytical methodology (HPLC, LC-MS-MS) has been used to survey the impurity profile of the intermediate and ensure that purging of impurities from subsequent drug substance manufacturing steps has occurred.
4. There is no change in the route of synthesis of the intermediate (including reagents, solvents or process conditions). The impurity profile of the intermediate remains the same (no new unidentified impurities above the VICH GL10 identification threshold, and no new identified impurities).

Supporting data

1. (1.2.5) Evidence of Good Manufacturing Practices (GMP) compliance status and/or Establishment Licence (EL) information. For more information, refer to the Notice: Submission Filing Recommendations for Veterinary Drugs - Good Manufacturing Practices and Drug Establishment Licences
2. (S.2.1) Name and address of the intermediate manufacturer.
3. (S.2.2) Route of synthesis of the intermediate.
4. (S.2.4) Specifications for the intermediate.
5. (S.2.4, S.4.4) Analytical data to support consistent impurity profiles between the previously authorized and new intermediate, and between drug substance manufactured with the previously authorized and new intermediate.
6. (S.2.5, S.2.6, S.3.2) The new source(s) of intermediate (or new sources of reagents/catalysts or solvents have been used during drug substance manufacture, validation, and technology transfer (if applicable). Applicable process validation studies are successfully completed to manufacture commercial size batches of the drug substance. Potential impurities not routinely tested have been confirmed to be absent from the impurity profile of the drug substance by either testing, risk analysis, or knowledge of fate/purge of impurities. Validation reports demonstrate equivalency of processes.
7. (S.2.6) Risk assessments and justification of changes (including those that result in changes the specifications of the related intermediate or the final drug substance).

4. Changes to the drug substance manufacturing site

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Replacement or addition of a manufacturing site	None	1-8	Supplement
	2-4	1,3-8	Notifiable Change
	1-4	1,3-8	Annual Notification
Addition of testing (such as release, stability) site	None	1,4,6,7	Notifiable Change
	5 or 6	1,4,6,7	Annual Notification
Deletion of a manufacturing site	None	None	Annual Notification

Conditions

1. No major changes in the drug substance synthesis. That is, it uses the same:
   • starting material
   • intermediates
   • solvents
   • reagents
   • purification/isolation process
   • process conditions and controls
   • analytical methods
   • specifications
2. Where materials of human or animal origin are used in the process:
   • the change of source is supported by a valid Transmissible Spongiform Encephalopathy (TSE) Certificate of Suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM), or
   • the source of the material from the new supplier has been previously authorized for viral safety or TSE risk by:
     • the Pharmaceutical Drugs Directorate (PDD) or
     • the Biological and Radiopharmaceutical Drugs Directorate (BRDD)
3. The change does not concern a sterile drug substance.
4. The change concerns drug products containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).
5. The analytical method(s) for the new testing site is/are equivalent to the analytical method(s) in the compendial drug substance monograph (Schedule B of the Food and Drug Regulations).
6. All analytical tests and equipment are equivalent to previously validated /registered methods.

Supporting data

1. (1.2.5) Evidence of GMP compliance status and/or Establishment Licence (EL) information. For more information, refer to the Notice: Submission Filing Recommendations for Veterinary Drugs - Good Manufacturing Practices and Drug Establishment Licences.
2. For sterile drug substances, evidence of validation of the sterilization process.
3. (S) A complete Active Substance Master File (ASMF) or drug substance information relevant to the change for the proposed site.
4. (S.2.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing, packaging and testing.
5. (S.2.3) For drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [such as ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk should be provided where available. For example:
   • name of manufacturer
   • species and tissues from which the material is a derivative
   • country of origin of the source animals
   • its use and previous acceptance
6. (S.4.3) Copies and summaries of method validation reports / method transfer reports, which demonstrate equivalency of analytical procedures used by the currently approved and proposed sites.
7. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and comparative analytical data in a tabular format, for at least 1 pilot scale batch of the currently approved and proposed sites.
8. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance at the new site into the long-term stability program (bracketing and matrixing with justification would be acceptable for multiple strength products).

5. Changes to the drug substance when the manufacturing site has a valid Certificate of Suitability (CEP)

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition of a manufacturing site or a change to the manufacturing process	1	1-5	Annual Notification
Replacement of a currently approved ASMF with a CEP	1,2	1,2	Annual Notification

Conditions

1. A valid Certificate of Suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM), along with the annexes and all attestations as described in Health Canada's guidance document "Use of Certificates of Suitability as Supporting Information in Drug Submissions".
2. No significant change to the drug substance information approved by Health Canada in the ASMF.

Supporting data

1. (1.2.3) A copy of the Certificate of Suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM) which is current and valid (the CEP has not been suspended or withdrawn). If the CEP is in lieu of an Active Substance Master File (ASMF), the declaration of access box shows the drug product manufacturer's name. The changes to the drug substance have been accepted by the EDQM as part of the certification procedures. Annexes and all attestations as described in Health Canada's guidance document "Use of Certificates of Suitability as Supporting Information in Drug Submissions".
2. (1.2.5) Evidence of Good Manufacturing Practices (GMP) and/or Establishment Licence (EL) information. For more information, refer to the Notice: Submission Filing Recommendations for Veterinary Drugs - Good Manufacturing Practices and Drug Establishment Licences.
3. (S.2.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and/or testing.
4. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and comparative analytical data in a tabular format, for at least 1 pilot scale batch of the currently approved and proposed sites (processes).
5. (P.8.2) An updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product manufactured using the drug substance manufactured at the new site or using the new process into the long-term stability program (bracketing and matrixing with justification would be acceptable for multiple strength products).

6. Change in the manufacturing process for the drug substance

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the manufacturing process for the drug substance	1	1-10	Supplement
	1-4,7,8	1-5,7,8,10	Notifiable Change
	1-8	1-5,7,8,10	Annual Notification

Conditions

1. No change in the identicality of the drug substance in accordance with the Health Canada's Interpretation of identical medicinal ingredient.
2. No change in the physical state of the drug substance. For example:
   • crystalline
   • amorphous
   • solid
   • semi-solid
   • liquid
   • gas
3. For low solubility drug substances, no change in the polymorphic form or no change in the particle size distribution of the drug substance.
4. Where materials of human or animal origin are used in the process:
   • the change of source is supported by a valid Transmissible Spongiform Encephalopathy (TSE) Certificate of Suitability (CEP) issued by the European Directorate for the Quality of Medicines (EDQM), or
   • the source of the material from the new supplier has been previously authorized for viral safety or TSE risk by:
     • the Pharmaceutical Drugs Directorate (PDD) or
     • the Biological and Radiopharmaceutical Drugs Directorate (BRDD)
5. No Level I or Level II changes in the drug substance specifications.
6. No change in the route of synthesis (intermediates remain the same), physical characteristics, and impurity profile of the drug substance (no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within VICH limits).
7. The change does not concern a sterile drug substance.
8. The change concerns drug products containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).

Supporting data

1. (S) Updated or new Master File (MF) (with a Letter of Access) or relevant drug substance information.
2. (S.2.2) Flow diagram of the proposed synthetic process(es) and a brief narrative description of the proposed manufacturing process(es).
3. (S.2.3) Information on the quality and controls of the materials used in the manufacture of the proposed drug substance, as applicable. For example, raw materials, starting materials, solvents, reagents, catalysts. If the information is proprietary, reference should be made to the restricted part of the MF, or the proprietary information may be submitted by the drug substance manufacturer directly to VDD.
4. (S.2.3) For drug substances or intermediates manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents (such as ruminant origin), information and evidence that the material does not pose a potential BSE/TSE risk should be provided where available. For example:
   • name of manufacturer
   • species and tissues from which the material is a derivative
   • country of origin of the source animals
   • its use and previous acceptance
5. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance. If the information is proprietary:
   • reference should be made to the restricted part of the MF, or
   • the proprietary information may be submitted, by the drug substance manufacturer, directly to VDD
6. (S.2.5) For sterile drug substances, evidence of validation of the sterilization process.
7. (S.3.1) Evidence for elucidation of structure, where applicable.
8. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and comparative analytical data in a tabular format, for at least 1 pilot scale batch of the currently approved and proposed processes.
9. (S.7.3) Results of 2 batches with a minimum of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing of the proposed drug substance.
10. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product, manufactured using the proposed drug substance, into the long-term stability program (bracketing and matrixing with justification would be acceptable for multiple strength products).

7. Change in the batch size for the drug substance

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the batch size for the drug substance	None	1-3	Notifiable Change
	1-7	1,3	Annual Notification

Conditions

1. No change in the proportionality of the raw materials.
2. Changes to the method of manufacture are only those necessitated by change in batch size (for example, use of different-sized equipment).
3. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
4. No Level I or Level II changes in the drug substance specifications.
5. Up to 10-fold scale-up or scale-down compared to the approved batch size.
6. The change concerns drug products containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).
7. The change does not concern a sterile drug substance.

Supporting data

1. (S.2.2) A brief narrative description of the proposed manufacturing process(es).
2. (S.2.5) For sterile drug substances, evidence of validation of the sterilization process.
3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least 1 pilot scale batch.

8. Change in the controls for the materials used in the manufacture of the drug substance or controls performed at critical steps in the process

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the controls for the materials used in the manufacture of the drug substance (such as raw materials, starting materials, solvents, reagents, catalysts) Change in the controls performed at critical steps in the process	None	1-4	Notifiable Change
	1-3	1,2,4	Annual Notification

Conditions

1. No Level I or Level II changes in the drug substance specifications, such as:
   • no new impurity above 0.1%
   • no change in the approved total impurity limit
   • residual solvents within VICH limits
2. The change does not affect the sterilization procedures of a sterile drug substance.
3. The change concerns drug products containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).

Supporting data

1. (S.2.3) Information on the quality and controls of the materials (such as raw materials, starting materials, solvents, reagents, catalysts) used in the manufacture of the proposed drug substance. If the information is proprietary:
   • reference should be made to the restricted part of the MF, or
   • the proprietary information may be submitted by the drug substance manufacturer, directly to VDD
2. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance. If the information is proprietary:
   • reference should be made to the restricted part of the MF, or
   • the proprietary information may be submitted by the drug substance manufacturer, directly to VDD
3. (S.2.5) For sterile drug substances, evidence of validation of the sterilization process.
4. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for at least 1 pilot scale batch of the drug substance manufactured with the current and proposed methods.

3.2.S.3 Characterisation

There are no quality change examples for this section at the present time that have not been addressed in other sections.

3.2.S.4 Control of the drug substance

9. Change regarding the standard claimed for the drug substance

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the standard claimed for the drug substance (for example, from a Professed to a Schedule B pharmacopoeial standard or from one Schedule B standard to a different Schedule B standard).	1-3	1-4	Annual Notification
Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph	1,2	1-3	Annual Notification

Conditions

1. The change is made exclusively to comply with the pharmacopoeia.
2. No Level I or Level II changes to the specifications [functional properties of the drug substance, such as particle size distribution, polymorphic form].
3. No deletion of or relaxation to any of the tests, analytical procedures, or acceptance criteria of the approved specification.

Supporting data

1. (S.4.1) Updated, QC approved, proposed drug substance specification.
2. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least 1 batch if new tests and/or analytical methods are implemented.
4. (S.4.5) Justification of the proposed drug substance specification (for example, demonstration of the suitability of the monograph to control the drug substance, including impurities).

10. Change in the specification for the drug substance involving test and acceptance criteria

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
For sterile drug substances, replacing the sterility test with alternate microbiological methods or process parametric release	None	1-8	Supplement
Deletion of a test	None	2,7,8	Notifiable Change
	1,5	2,7,8	Annual Notification
Replacement of a test	1-7	2-5,7,8	Annual Notification
Addition of a test	1,3,4,6,7	2-5,7,8	Annual Notification
Relaxation of an acceptance criterion	None	2,7,8	Notifiable Change
	1,4,6,7	2,7,8	Annual Notification
Tightening of an acceptance criterion	1,2,4,6,7	2,7,8	Annual Notification

Conditions

1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
2. The change is within the range of approved acceptance criteria.
3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
4. No change in the impurity profiles that impacts safety of the drug substance. Acceptance criterion for any Class 3 residual solvent is within the VICH limits (the relaxation of an acceptance criterion for a Class 1 or 2 solvent should be filed as a Notifiable Change).
5. The deleted test has been demonstrated to be redundant with respect to the remaining tests.
6. The change does not concern sterility testing.
7. The change concerns drug products containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).

Supporting data

1. (S.2.5) Evidence of validation of the sterilization process.
2. (S.4.1) Updated, QC approved, proposed drug substance specification.
3. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
4. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
5. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
6. (S.4.4) Description of the batches, certificates of analyses, or batch analysis report and summary of results, of a sufficient number of batches (minimum of 10 batches) to support the process parametric release.
7. (S.4.5) Justification of the proposed drug substance specification (such as test parameters, acceptance criteria or analytical procedures). For Process Parametric Release (PPR), provide a thorough risk assessment that identifies the risks of manufacturing and releasing non-sterile product and the proposed management plan. For further information on requirements for obtaining authorization for PPR, consult Health Canada's Guidance on Parametric Release - Pharmaceutical Inspection Co-Operation Scheme (PIC/S).
8. (P.2) Where appropriate (such as for a change in particle size limit for a poorly soluble drug substance), comparative, multi-point dissolution profiles in the release medium for 1 batch of the drug product using material from the approved and change drug substance specifications.

11. Change in the specification for the drug substance involving analytical procedures

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Deletion of an analytical procedure	None	1,5	Notifiable Change
	5	1,5	Annual Notification
Replacement of, alternate, or additional analytical procedure	None	1-5	Notifiable Change
	1-4	1-5	Annual Notification
Change from a House analytical procedure to a Schedule B analytical procedure, a change from an approved compendial analytical procedure to an harmonized compendial procedure, or from one Schedule B standard to a different Schedule B standard).	None	1,3-5	Annual Notification

Conditions

1. The method of analysis is based on the same analytical technique or principal and no new impurities are detected.
2. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
4. The change does not concern sterility testing.
5. The deleted analytical procedure is an alternate and equivalent method.

Supporting data

1. (S.4.1) Updated, QC approved, proposed drug substance specification.
2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
3. (S.4.3) Copies or summaries of method validation reports, if new analytical procedures are used.
4. (S.4.3) Comparative analytical results demonstrating that the approved and proposed analytical procedures are equivalent.
5. (S.4.5) Justification of the proposed drug substance specification.

3.2.S.6 Container closure system

12. Change in the primary container closure system(s) for the storage and shipment of the drug substance

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the primary container closure system(s) for the storage and shipment of the drug substance	None	1-3	Notifiable Change
	1,2	2,3	Annual Notification

Conditions

1. Results demonstrate that the proposed container closure system is at least equivalent to the approved container closure with respect to its relevant properties (such as including results of transportation or interaction studies, if appropriate).
2. The drug substance is not sterile or the change does not affect sterilization parameters of a sterile drug substance.

Supporting data

1. (S.2.5) Evidence of process validation for the sterilization process, if different from the current process.
2. (S.6) Information on the proposed container closure system (for example, description, materials of construction, specifications).
3. (S.7.3) Results of a minimum of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing of the drug substance in the proposed container closure system.

3.2.S.7 Stability

13. Change in the re-test period (or shelf-life) for the drug substance

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Extension	None	1-4	Notifiable Change
	1-2	1-4	Annual Notification
Reduction	1	1-4	Annual Notification

Conditions

1. The drug substance meets the approved stability specification.
2. Full long-term stability data is available covering the proposed re-test period (or shelf-life) and is based on stability data generated on at least 3 commercial scale batches.

Supporting data

1. (S.7.1) Summary of stability testing and results (for example, studies conducted, protocols used, results obtained).
2. (S.7.1) Proposed storage conditions and re-test period (or shelf-life, as appropriate).
3. (S.7.2) Updated post-approval stability protocol and stability commitment.
4. (S.7.3) Results of stability testing generated on at least 2 pilot and/or commercial scale batches with stability data to support the proposed re-test period or shelf-life.

14. Change in the storage conditions for the drug substance

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion (for example, from 15-25 °C to 15-30 °C).	None	1	Annual Notification

Conditions

None

Supporting data

1. (S.7.3) If applicable, stability testing results to support the change to the storage conditions on at least 2 lots (pilot or commercial scale).