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

On this page

• 3.2.P.1 Description and composition of the drug product
• 3.2.P.2 Pharmaceutical development
• 3.2.P.3 Manufacture
• 3.2.P.4 Control of excipients
• 3.2.P.5 Control of drug product
• 3.2.P.7 Container closure system
• 3.2.P.8 Stability
• 3.2.R.2 Devices

3.2.P.1 Description and composition of the drug product

15. Addition of a dosage form or strength

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition of a dosage form or strength	None	1-14	Supplement

Conditions

None

Supporting data

1. (1.5) Supporting clinical or comparative bioavailability data, in vitro in vivo correlation (IVIVC) data (or a request for a waiver of in vivo studies).
2. (1.2.5) Evidence of GMP compliance status and Establishment License (EL) Information. For more information, refer to the Notice: Submission Filing Recommendations for Veterinary Drugs - Good Manufacturing Practices and Drug Establishment Licences
3. (1.2.6) Letters of Access if Master Files (MFs), are submitted for new excipients.
4. Package Insert and Inner and Outer Labels.
5. (P.1) Description and composition of the dosage form.
6. (P.2) Discussion of the components of the drug product (such as choice of excipients, compatibility of drug substance and excipients), comparative in vitro testing (such as multi-point dissolution profiles in the release medium for solid dosage units) for the approved and proposed products, discussion of any in vitro and/or in vivo studies.
7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
8. (P 3.5) Process validation data on 3 consecutive commercial batches and /or QC approved Process validation protocol of the proposed drug product. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches per year). In addition, for a sterile drug product, evidence of validation for the sterilization process.
9. (P.4) Control of Excipients, if new excipients are proposed (such as specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations).
10. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for a minimum of 1 pilot scale batch per strength).
11. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
12. (P.8.1) Stability Summary and Conclusions (minimum of 2 pilot scale batches), results of a minimum of 6 months of accelerated (or intermediate as appropriate) and 6 months of long-term testing of the proposed drug product; bracketing and matrixing approaches for multiple strengths and packaging components could be applied, if scientifically justified.
13. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
14. (R.1) Executed Production Documents for at least 1 pilot scale batch of each new dosage form or strength.

16. Change in the composition of a solution dosage form

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the composition of a solution dosage form	2	1-13	Supplement
	1,3,4,5,7	2-13	Notifiable Change
	1,3-8	2-13	Annual Notification

Conditions

1. The changes in excipients of the approved and proposed drug products are considered to be qualitatively the same and quantitatively essentially the same (as defined in the Health Canada guidance document Pharmaceutical Quality of Aqueous Solution).
2. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
3. The proposed excipient(s) does/do not function as a preservative or preservative enhancer.
4. No Level I or Level II changes in the specifications of the proposed excipient(s) or the drug product.
5. No change to the physical characteristics of the drug product (such as viscosity, pH, osmolality).
6. The change does not concern a sterile drug product.
7. The change concerns a drug product containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).
8. The proposed colouring agent (if applicable) is permitted by the Canadian regulations (refer to the section C.01.040.2 of the Food and Drug Regulations).

Supporting data

1. Literature data or evidence to confirm that the change does not affect the absorption of the drug substance.
2. Supporting palatability data when a flavouring agent has been added, removed or replaced.
3. (1.2.6) Letters of Access if Master Files (MFs), are submitted for new excipients, when applicable.
4. Package Insert and Inner and Outer Labels, when applicable.
5. (P.1) Description and composition of the dosage form.
6. (P.2) Discussion of the components of the drug product (such as choice of excipients, compatibility of drug substance and excipients), comparative testing on the physicochemical properties for the approved and proposed products, results of preservative effectiveness testing (if applicable).
7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
8. (P.3.5) Process validation data on 3 consecutive commercial batches and /or QC approved Process validation protocol of the proposed drug product. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches per year). In addition, for a sterile drug product, evidence of validation for the sterilization process.
9. (P.4) Control of Excipients (for example, specifications with justification).
10. (P.5) Batch Analyses (certificate of analyses for a minimum of 1 pilot scale batch per strength).
11. (P.8.1) Stability Summary and Conclusions: results of a minimum of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing for at least 2 pilot scale batches of the proposed drug product.
12. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
13. (R.1) Executed Production Documents for at least 1 pilot scale batch of each strength of the proposed product.

17. Change in the composition of an immediate release dosage form (including a medicated premix)

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the composition of an immediate release dosage form (including a medicated premix)	4	1-13	Supplement
	1-5	2-13	Notifiable Change
	1-7	2-13	Annual Notification

Conditions

1. The changes in the excipients are considered to be qualitatively the same.
2. The quantitative changes in excipients, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 2.
3. The change does not affect the performance characteristics of the drug product.
4. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
5. No Level I or Level II changes in the specifications of the proposed excipient(s) or the drug product.
6. The change concerns a drug product containing drug substances that are discrete chemical entities (the drug substance is not a polymer or polymeric complex).
7. The proposed colouring agent (if applicable) is permitted by the Canadian regulations (refer to the section C.01.040.2 of the Food and Drug Regulations).

Supporting data

1. Literature data or evidence to confirm that the change does/do not affect the absorption of the drug substance.
2. Supporting palatability data when a flavouring agent has been added, removed or replaced
3. (1.2.6) Letters of Access if Master Files (MFs) are submitted for new excipients.
4. Package Insert and Inner and Outer Labels, when applicable.
5. (P.1) Description and composition of the dosage form.
6. (P.2) Discussion of the components of the drug product (such as choice of excipients, compatibility of drug substance and excipients), comparative in vitro testing for the approved and proposed products (for example, depending on the solubility and permeability of the drug (refer to Appendix 1), multi-point dissolution profiles in either the release medium or in multiple media covering the physiological pH range), discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
8. (P.3.5) Process validation data on 3 consecutive commercial batches and /or QC-approved Process validation protocol of the proposed drug product. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches per year). In addition, for a sterile drug product, evidence of validation for the sterilization process.
9. (P.4) Control of Excipients, if new excipients are proposed [such as specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
10. (P.5) Batch Analyses (certificate of analyses for a minimum of 1 pilot scale batch per strength).
11. (P.8.1) Stability Summary and Conclusions (minimum of 2 pilot scale batches): results of a minimum of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing of the proposed drug product (bracketing or matrixing approaches for multiple strengths and packaging components could be applied, if scientifically justified).
12. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
13. (R.1) Executed Production Documents for 1 batch representative of each strength of the proposed product.

18. Addition, deletion or replacement of micro tracer used in a medicated premix

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition, deletion or replacement of micro tracer used in a medicated premix	1	1-4	Annual Notification

Conditions

1. The proposed micro tracer is pre-tested to confirm stability in the drug premix, and there is no change in the stability protocol, stability tests, and stability commitment of the medicated premix.

Supporting data

1. Justification of the addition/removal or replacement of the micro tracer (for example, demonstration of the suitability of the new micro tracer to control the medicated premix, including batch to batch consistency). Justification that there is no "statistically significant" deviation from complete mixing.
2. Information supporting adequacy of batch-to-batch cleanout of the mixer and other feed manufacturing equipment.
3. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, process validation data and/or QC approved Process Validation Protocol. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches per year).
4. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.

19. Change to the composition of a modified release dosage form

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change to the composition of the release controlling agent in a modified release dosage form	None	1-12	Supplement
	1,2	1-12	Notifiable Change

Conditions

1. The change is within parameters established by an in vitro in vivo correlation previously approved by Health Canada.
2. No changes in the specification of the drug product other than appearance or changes to comply with a Schedule B monograph.

Supporting data

1. (1.5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vitro in vivo correlation has been established and approved).
2. (1.2.6) Letters of Access if Master Files (MFs) are submitted for new excipients.
3. Package Insert and Inner and Outer Labels, when applicable.
4. (P.1) Description and composition of the dosage form.
5. (P.2) Discussion of the components of the drug product (for example, choice of excipients, compatibility of drug substance and excipients), comparative in vitro testing, for example:
   • depending on the mechanism for drug release (extended or delayed)
   • drug release profiles in multimedia or using different agitation speeds) for the approved and proposed products
   • discussion of any in vitro and/or in vivo studies
   • results of preservative effectiveness testing (if applicable)
6. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
7. (P.3.5) Process validation data on 3 consecutive commercial batches and /or QC approved Process validation protocol of the proposed drug product. In addition, for a sterile drug product, evidence of validation for the sterilization process. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
8. (P.4) Control of Excipients, if new excipients are proposed (for example, specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations).
9. (P.5) Batch Analyses (certificate of analyses for a minimum of 1 pilot scale batch per strength).
10. (P.8.1) Stability Summary and Conclusions (minimum of 2 pilot scale batches). For example, results of a minimum of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing of the proposed drug product.
11. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
12. (R.1) Executed Production Documents for 1 batch of each strength.

20. Change to product markings, involving a change in embossing, debossing, or engraving (except scorelines/break lines) or a change in imprinting

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change to product markings, involving a change in embossing, debossing, or engraving, except scorelines/break lines (for example, plain tablet to engraved, engraved to plain, change in engraving), or a change in imprinting (for example, plain tablet/capsule to imprinted tablet/capsule)	1,2	1-3	Annual Notification

Conditions

1. The change does not affect the stability or performance characteristics (such as release rate) of the drug product.
2. Changes to the drug product specifications are those necessitated only by the change to the markings.

Supporting data

1. Package Insert and Inner and Outer Labels.
2. (P.5) Specification(s) and Batch Analysis (such as Certificate of Analysis for 1 batch per strength).
3. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).

21. Change in scoring configuration

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition of a scoreline	1,3	1-6	Notifiable Change
Deletion of a scoreline	1-4	1,4-6	Annual Notification

Conditions

1. The change does not affect the stability or performance characteristics (such as release rate) of the drug product.
2. Changes to the drug product specifications are those necessitated only by the change to the scoring.
3. The change does not concern a modified release drug product.
4. Addition or deletion of a score line to a generic product is consistent with a similar score line in the innovator product (Canadian Reference Product).

Supporting data

1. Package Insert and Inner and Outer Labels.
2. (P.2) Comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
3. (P.2) Demonstration of the uniformity of the dosage units of the split tablets.
4. (P.5) Specification(s) and Batch Analysis (such as Certificate of Analysis for 1 batch per strength).
5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
6. (R.1) Executed Production Documents for 1 batch representative of each strength of the proposed product.

22. Change in shape or dimensions of tablets, capsules, suppositories, or pessaries

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in shape or dimensions of tablets, capsules, suppositories, or pessaries	1,2	1-6	Notifiable Change
	1-3	1-6	Annual Notification

Conditions

1. No change in the qualitative and quantitative composition and mean mass or fill weight.
2. Changes to the drug product specifications are those necessitated by the change to the drug product shape or dimensions.
3. The change does not concern a modified release drug product or does not affect the performance characteristics (such as release rate) of the drug product.

Supporting data

1. Package Insert and Inner and Outer Labels, when applicable.
2. (P.2) Discussion of the differences in manufacturing process(es) between the approved and proposed products and the potential impact on product performance
3. (P.2) Comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
4. (P.5) Specification(s) and Batch Analysis (such as Certificate of Analysis for 1 batch per strength).
5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
6. (R.1) Executed Production Documents for 1 batch representative of each strength of the proposed product.

23. Change in diluent

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
replacement or addition of a diluent for a lyophilized powder or concentrated solution	None	1-11	Supplement
	1	2,4,8	Notifiable Change
deletion of a diluent	None	2	Annual Notification

Conditions

1. Diluent is commercially available with a valid Drug Identification Number (DIN).

Supporting data

1. (1.2.6) Letters of Access if Master Files (MFs) are submitted for new excipients.
2. Package Insert and Inner and Outer Labels.
3. (P.1) Description and composition of the diluent.
4. (P.2) Discussion of the components of the drug product, as appropriate (such as choice of excipients, compatibility of the drug product with the diluent).
5. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, process validation data and/or QC approved Process Validation Protocol, and testing standards for the diluent if it is included with the product. Concurrent validation would be acceptable for low volume drug products (such as only 2 batches per year).
6. (P.4) Control of Excipients, if new excipients are proposed (such as specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations).
7. (P.5) Batch Analyses (such as Certificate of Analysis for a minimum of 1 pilot scale batch of the diluent, if it is included with the product.
8. (P.7) Discussion (including description, materials of construction on the container closure system, compatibility studies with the diluent).
9. (P.8.1) Stability Summary and Conclusions: results for 2 pilot scale batches of a minimum of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing of the diluent.
10. (P.8.2) Updated post-approval stability protocol and stability commitment for the diluent if it is included with the product.
11. (R.1) Executed Production Documents for 1 batch of the diluent if it is included with the product.

3.2.P.2 Pharmaceutical development

24. Change in the approved design space

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Establishment of a new design space	None	1	Supplement
Expansion of the approved design space	None	1	Supplement
Reduction in the approved design space (any change that reduces or limits the range of parameters used to define the design space)	None	1	Notifiable Change
Process parametric release	None	1	Supplement

Conditions

None

Supporting data

1. (P.2) Pharmaceutical development data to support the establishment or changes to the design space (including changes to process parametric release for sterile products). For changes to 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 the Health Canada's Guidance on Parametric Release - Pharmaceutical Inspection Co-Operation Scheme (PIC/S).

3.2.P.3 Manufacture

25. Replacement or addition of a drug product manufacturer / manufacturing site

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Production of a modified release, product with a complex matrix (such as emulsions, extended release parenterals, implants) or sterile product	None	1-10	Supplement
	1	2-10	Notifiable Change
Production of an immediate release product (for example, tablet, capsule, liquids, semi-solids)	None	2-10	Notifiable Change
	1-4	2-5,7-10	Annual Notification
Primary packaging	2,3	2,5	Annual Notification
Testing (such as release, stability)	None	2,5,7-9	Notifiable Change
	5 or 6	2,5,7-9	Annual Notification
Storage and distribution	1-3	2,3,5	Annual Notification

Conditions

1. No change in the Batch Formula, Description of Manufacturing Process, Equipment Class and Process Controls, Controls of Critical Steps and Intermediates, or Drug Product Specifications.
2. No Level I change in the container closure system.
3. The proposed facility has a current satisfactory Canadian GMP rating as determined by the Health Product Compliance Directorate, ROEB, GMP screening acceptance notice (at "Day 90") from the ROEB, or is already included in the Establishment License.
4. 3 consecutive production scale batches have been successfully validated as per QC approved process validation protocol, and technical transfer and/or process validation reports at the proposed site are available. Concurrent validation would be acceptable for low volume drug products (such as only 2 batches manufactured per year).
5. The analytical method(s) for the new testing site is/are equivalent to the analytical method(s) in the compendial drug product monograph (Schedule B of the Food and Drug Regulations).
6. All analytical tests are equivalent to previously validated /registered methods.

Supporting data

1. (1.5) Supporting clinical or comparative bioavailability data (or a request for a waiver of in vivo studies) (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vivo/in vitro correlation has been established).
2. (1.2.5) Evidence of GMP compliance status and Establishment License (EL) Information. For more information, refer to the Notice: Submission Filing Recommendations for Veterinary Drugs - Good Manufacturing Practices and Drug Establishment Licences.
3. (P) Confirmation that information on the drug product has not changed as a result of the submission (for example, other than change in site).
4. (P.2) Comparative in vitro testing (such as multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids) for one batch of each strength of the approved and of the product produced at the new site (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified). See Appendix 1 for additional detail.
5. (P.3.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing, packaging, testing, storage and/or distribution.
6. (P.3.5) Process validation data on 3 consecutive commercial scale batches of the product at the new site and/or QC approved process validation protocol; in addition, for a sterile product, evidence of validation for the sterilization process. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
7. (P.5.3) Copies and summaries of method validation reports / method transfer reports, which demonstrate equivalency of analytical procedures used by the currently approved and proposed sites.
8. (P.5.4) Certificate of analyses for at least 1 commercial scale batch (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the product produced and/or tested at the new site (as applicable) into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
10. (R.1) Executed Production Documents for at least 1 commercial scale batch of each strength of the proposed product.

26. Change in the batch size for the drug product

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Increase in batch size beyond a factor of 10 times for a modified release drug product	None	1-7	Supplement
Increase in batch size beyond a factor of 10 times for an immediate release drug product	1-5	2,3,5-7	Annual Notification
Increase in batch size, up to and including a factor of 10 times	4	2,3,5-7	Annual Notification
A downscaling in the batch size	1-3,5	2-7	Annual Notification

Conditions

1. Any changes to the manufacturing process and/or to the in-process controls are only those necessitated by the change in batch size, (such as use of different sized equipment.)
2. The change should not be a result of unexpected events, resulting in failure to meet specifications, arisen during manufacture, or because of stability concerns.
3. The change in batch size is in comparison to the pivotal clinical/biobatch, or to the approved and validated commercial scale batches.
4. 3 consecutive production scale batches have been successfully validated as per QC approved process validation protocol. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
5. The change does not affect the sterilization procedure of a sterile drug product.

Supporting data

1. (1.5) Supporting clinical or comparative bioavailability data (or a request for a waiver of in vivo studies).
2. (P.2) Comparative in vitro testing (for example, multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids) for one batch of each strength of the approved and at the proposed scale.
3. (P.3.2) Batch formula of the proposed dosage form.
4. (P.3.5) Process validation data on 3 consecutive production scale batches of the proposed drug product and /or QC approved process validation protocol. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year). Confirmation that the reference batch size has been previously validated, as per approved process validation protocol; in addition, for sterile products, evidence of validation for the sterilization process.
5. (P.5.4) Description of the batches and summary of results for at least 1 commercial scale batch at the proposed scale.
6. (P.8.2) Updated post-approval stability protocol (QC approved) and stability commitment to place the first commercial scale batch of each strength at the proposed scale into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
7. (R.1.2) Executed Production Documents for at least 1 commercial scale batch of each strength of the proposed product.

27. Change in the drug product manufacturing process

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the drug product manufacturing process	None	1-8	Supplement
	1-5	2-8	Notifiable Change
	1-8	2,3,5-8	Annual Notification

Conditions

1. The change does not affect the performance of the drug product.
2. The manufacturing processes for the approved and proposed products use the same principles and the same classes of equipment (note: a change from wet to dry granulation, from direct compression to wet/dry granulation, or vice versa, would be considered in principle).
3. Changes to equipment, operating procedures and process controls are minor/non-critical. The equipment used to produce the proposed product may vary in capacity, but are of the same class and operating principles.
4. The change is not the result of unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
5. The change does not involve the packaging or labelling where the primary packaging provides a metering and/or delivery function.
6. 3 consecutive commercial scale batches have been successfully validated as per QC-approved process validation protocol (this condition could be waived with justification for minor/non-critical changes as outlined in Condition #3). Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
7. The change does not concern a modified release drug product.
8. The change does not affect the sterilization procedure of a sterile drug product.

Supporting data

1. (1, 5) Supporting clinical or comparative bioavailability data.
2. (P.2) Discussion of:
   • the development of the manufacturing process, where applicable
   • comparative in vitro testing for the approved and proposed products, such as:
     • multi-point dissolution profiles in the release medium for solid dosage units
     • particle size distribution
     • comparative diffusion test results for semi-solids
   • any in vitro and/or in vivo studies, where applicable
3. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
4. (P.3.5) Process validation data on 3 consecutive production scale batches of the drug product and or QC approved process validation protocol. For sterile products, evidence of validation and/or evaluation studies for the sterilization process. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
5. (P.5) Specification(s) (if specification(s) have changed), Batch Analyses (certificate of analyses for at least one commercial scale batch per strength).
6. (P.8.1) Stability Summary and Conclusions:
   • For a major change to the manufacturing process (for example, change in equipment class or manufacturing principles), results for 2 pilot scale batches of a minimum of:
     • 3 months of accelerated (or intermediate as appropriate) and
     • 3 months of long-term testing of the proposed drug product (bracketing and matrixing may be applied, if scientifically justified)
   • For a minor change to the manufacturing process (such as a change in mixer stirring speed), stability data at the time of filing would not be necessary (see P.8.2 below). Bracketing and matrixing may be applied, if scientifically justified.
7. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
8. (R.1.2) Executed Production Documents for at least 1 commercial scale batch of each strength of the proposed product.

28. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Deletion of a test	1,4,5	1,4	Annual Notification
Replacement or addition of a test	1-4,6	1-4	Annual Notification
Relaxation or tightening of an acceptance criterion	1,4	1-4	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 (applies to replacement, not to addition of a test, where applicable).
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 affect the sterilization parameters or procedures of a sterile drug product.
5. The deleted analytical procedure has been demonstrated to be redundant with respect to the remaining analytical procedures (such as colour), and does not pertain to a critical quality attribute of the product (such as blend uniformity, weight variation).
6. The replaced or added analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.

Supporting data

1. (P.3.3) Description of the proposed process controls or acceptance criteria of the critical steps and intermediates.
2. (P.3.5) Process validation data and /or QC approved Process validation protocol of the proposed drug product. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
3. (P.5.4) Description of the batches, and certificate of analyses for at least 1 commercial scale batch.
4. (R.1.2) Executed Production Documents for at least 1 batch of each strength of the proposed product or Master Production Documents.

29. Change in the approved protocol for process validation and/or evaluation studies

Description of Change	Conditions to be Fulfilled	Supporting Data	Reporting Category
Change in the approved protocol for process validation and/or evaluation studies	1,2	1	Annual Notification

Conditions

1. The change does not concern a modified release drug product.
2. The change does not affect the sterilization procedures of a sterile drug product.

Supporting Data

1. (P.3.5) QC approved revised process validation and/or evaluation studies. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).

3.2.P.4 Control of excipients

30. Change in the source of an excipient

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the source of an excipient from a vegetable, synthetic source, or non-TSE (such as animal) to a TSE risk (such as animal) source, or from a TSE risk (such as animal) to a different TSE risk (such as a different animal) source	None	2-4	Notifiable Change
	1,2	2-4	Annual Notification
Change in the source of an excipient from a TSE risk (such as animal) source to a vegetable or synthetic source	None	1,3	Annual Notification

Conditions

1. There is no qualitative or quantitative change in the excipient.
2. 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 excipient is obtained from a previously approved source.

Supporting data

1. Declaration from the manufacturer of the excipient that it is entirely of vegetable or synthetic origin.
2. Details of the source of the excipient (animal species, country of origin) and the steps undertaken in processing to minimize the risk of TSE exposure.
3. Information demonstrating comparability in terms of physico-chemical characterization of the proposed excipient with the approved excipient.
4. TSE Certificate of Suitability (CEP) issued by the EDQM, if available, or satisfactory BSE/TSE risk assessment on proposed excipient.

3.2.P.5 Control of drug product

31. Change regarding the standard claimed for the drug product

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the standard claimed for the drug product (for example, from a Professed to Schedule B pharmacopoeial standard)	1,2	1-5	Annual Notification
Change in the specification for the drug product to comply with an updated Schedule B pharmacopoeial monograph	1,2	2-5	Annual Notification

Conditions

1. The change is made exclusively to comply with the Schedule B pharmacopoeia monograph.
2. No change to the specification that results in a potential impact on the performance of the drug product.

Supporting data

1. Package Insert and Inner and Outer Labels.
2. (P.5.1) Updated, QC approved, proposed drug product specification.
3. (P.5.3) 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.
4. (P.5.4) Description of the batches, certificates of analyses, and summary of results, for at least 1 batch (minimum pilot scale) of the drug product tested according to the proposed specification.
5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program. Bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified.

32. Change in the specification for the drug product tests and acceptance criteria

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
For sterile products, replacing the sterility test with alternative microbiological methods or process parametric release	None	1,2,5,7-9	Supplement
Deletion of a test	1,4-7	2,8,9	Annual Notification
Replacement or addition of a test	1-4,6-8	2-6,8,9	Annual Notification
Relaxation of an acceptance criterion	None	2,5,6,8,9	Notifiable Change
	1,4,6-8	2,5,6,8,9	Annual Notification
Tightening of an acceptance criterion	1,4,6,7	2,8,9	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 (applies to replacement, not to addition of a test, where applicable).
3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
4. No changes in the impurity profile that impacts safety of the drug product. 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 and does not impact the safety or overall quality of the product [for example, removal of an organic volatile solvent test after at least 10 commercial scale batches tested and meet approved acceptance criteria, or provide valid scientific justification].
6. The change to the specifications does not affect the performance of the drug product.
7. The change does not concern sterility testing.
8. The relaxed criterion is in accordance with a Schedule B compendial monograph.

Supporting data

1. (P.3.5) Process validation data. Concurrent validation would be acceptable for low volume drug products (for example, only 2 batches manufactured per year).
2. (P.5.1) Updated, QC approved, proposed drug product specification.
3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
4. (P.5.3) Copies or summaries of method validation reports, if new analytical procedures are used.
5. (P.5.3) 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. (P.5.4) Description of the batches, and summary of results, for at least 1 (minimum pilot scale) of the drug product tested according to the proposed specification.
7. (P.5.4) Description of the batches, and summary of results, of a sufficient number of batches (at least 10 commercial scale batches) to support the process parametric release.
8. (P.5.6) Justification of the proposed drug product specification (for example, demonstration of the suitability to control the drug product, including degradation products). For Process Parametric Release (PPR), a 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 the Health Canada's Guidance on Parametric Release - Pharmaceutical Inspection Co-Operation Scheme (PIC/S).
9. For drug products that contain a drug substance that is not a discrete chemical entity (the drug substance is not a polymer or polymeric complex), demonstration that consistency of quality and of the production process is maintained.

33. Change in the specification for the drug product regarding analytical procedures

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Deletion of an analytical procedure	5	1,6	Notifiable Change
	5,6	1,6	Annual Notification
Replacement, alternate, or additional analytical procedure	None	1-6	Notifiable Change
	1-5	1-6	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).	1,3	1-6	Annual Notification

Conditions

1. No change in the approved acceptance criteria.
2. The method of analysis is based on the same analytical technique or principal and no new impurities are detected (Refer to VICH GL11 for impurity thresholds).
3. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
4. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
5. The change does not concern sterility testing nor does it impact the dissolution test condition (such as apparatus, speed, medium) for a modified release product.
6. The deleted analytical procedure has been demonstrated to be redundant with respect to the remaining procedures and does not impact the safety or overall quality of the product (for example, removal of an organic volatile solvent test after at least 10 commercial scale batches tested and meet acceptance criteria, or provide valid scientific justification).

Supporting data

1. (P.5.1) Updated, QC approved, proposed drug product specification.
2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
4. (P.5.3) 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.
5. (P.5.4) Description of the batches, and summary of results, for at least 1 batch (minimum pilot scale) of the drug product tested according to the proposed specification, if applicable.
6. (P.5.6) Justification of the proposed drug product specification (for example, demonstration of the suitability to control the drug product, including degradation products), if applicable.

34. Change of specification for a veterinary drug product used in food producing animals

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change of specification for a veterinary drug product used in food producing animals	None	1-8	Supplement
	4,6	1,4,5,8,9	Notifiable Change
	1-5	1,4,5,8,9	Annual Notification

Conditions

1. The change is not necessitated by unexpected events arising during manufacture or because of stability concerns.
2. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
3. Acceptance criteria for degradation products and any Class 3 residual solvents are within the VICH GL 10, VICH GL 11 and VICH GL 18 limits, where applicable (the relaxation of an acceptance criterion for a Class 1 or 2 solvent should be filed as a Notifiable Change).
4. The change to the specifications does not result in a potential impact on the performance of the drug product (for example, solubility, release rate, dissolution).
5. The change does not concern sterility testing.
6. The change does not affect the withdrawal period (or withholding time for milk) of the veterinary drug product.

Supporting data

1. (P.5.1) Updated, QC approved, proposed drug product specification.
2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
4. (P.5.3) 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.
5. (P.5.4) Description of the batches, certificates of analyses, and summary of results, in a tabular format, for at least 1 batch (minimum pilot scale) of the drug product tested according to the proposed specification.
6. (P.5.4) Description of the batches, certificates of analyses, and summary of results, in a tabular format, of a sufficient number of batches (at least 10 commercial scale batches) to support the process parametric release, where applicable.
7. (P.5.6) Justification of the proposed drug product specification (for example, demonstration of the suitability of the monograph to control the drug product, including degradation products). 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 the Health Canada's Guidance on Parametric Release - Pharmaceutical Inspection Co-Operation Scheme (PIC/S).
8. For drug products that contain a drug substance that is not a discrete chemical entity (the drug substance is not a polymer or polymeric complex), demonstration that consistency of quality and of the production process is maintained.
9. Confirmation that the withdrawal period (or withholding time for milk) has not been affected as a result of the change.

3.2.P.7 Container closure system

35. Change from an approved single-dose container to multi-dose container including in-use stability period

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change from an approved single-dose container to multi-dose container including in-use stability period	1	1-6	Notifiable Change

Conditions

1. The change does not involve a functional container closure system (for example, pre-filled auto injector).

Supporting data

1. Package Insert and Inner and Outer Labels.
2. (P.2) Information demonstrating suitability of the proposed container/closure system for its intended use (evidence that it is meeting the relevant pharmacopoeial tests, for example:
   • USP <661> Plastic Packaging Systems and their materials of construction
   • USP <1663> and <1664> Extractables and Leachables
   • USP <87> Biological Reactivity Tests, In Vitro
   • USP <88> Biological Reactivity Tests, In Vivo, as applicable
   • USP <381> Elastomeric Closures for Injections
   • USP <671> Containers - Performance Testing
   • Description of any additional treatments such as sterilization and depyrogenation of the components
3. (P.7) Information on the proposed container closure system, as appropriate [such as description, materials of construction of primary/secondary packaging components, performance specifications].
4. (P.3.5) For sterile products, process validation and/or evaluation studies, or provide equivalency rationale. For a secondary functional container closure system, validation testing report.
5. (P.8.1) Summary of stability testing and results [such as studies conducted, protocols used, results obtained].
6. (P.8.3) Stability test results from:
   • accelerated testing (usually a minimum of 3 months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and
   • 3 months of real time/real temperature testing on 3 drug product batches stored in the proposed container, or longer if less than 3 time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long-term stability studies.

Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to VICH GL45).

36. Replacement or addition of a primary container closure system and change to the package size

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Replacement or addition of a primary container closure system	None	1-6	Notifiable Change
	1-4	1,2,4,6	Annual Notification
Change in the package size involving change in the fill weight / fill volume	None	1-7	Notifiable Change
	1-4	1,2,4-7	Annual Notification
Change in the package size involving a change in the number of units (such as tablets, ampoules) per package	None	1-6	Notifiable Change
	1-4	1,2,4-6	Annual Notification

Conditions

1. The change does not concern a sterile product.
2. No change in the type of container closure or materials of construction.
3. The change does not concern a container closure that functions to meter the drug product.
4. The change is consistent with the posology and treatment duration.

Supporting data

1. Package Insert and Inner and Outer Labels, when applicable.
2. (P.2) Information demonstrating the suitability of the proposed container closure system for its intended use (evidence that it is meeting the relevant pharmacopoeial tests, such as:
   • USP <661> Plastic Packaging Systems and their materials of construction
   • USP <1663> and <1664> Extractables and Leachables
   • USP <87> Biological Reactivity Tests, In Vitro
   • USP <88> Biological Reactivity Tests, In Vivo, as applicable
   • USP <381> Elastomeric Closures for Injections
   • USP <671> Containers - Performance Testing
   • Description of any additional treatments such as sterilization and depyrogenation of the components

   For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.

3. (P.3.5) For sterile products, evidence of the sterilization process for the container closure system and validation data of the manufacturing process for the new additional package size, where applicable.
4. (P.7) Information on the proposed container closure system (such as description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate).
5. (P.8.1) Stability Summary and Conclusions, results of a minimum 2 pilot scale batches, of 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing and, where applicable, results of photostability studies. Bracketing and matrixing approaches can be used for multiple strengths and packaging components if scientifically justified.
6. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
7. Rationale for the additional package size.

37. Change in qualitative and/or quantitative composition of any primary or functional secondary container closure component

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in qualitative and/or quantitative composition of any primary or functional secondary container closure component	None	1-6	Notifiable Change
	1,2	1,2,4,6	Annual Notification

Conditions

1. The proposed packaging is at least as protective as the approved packaging.
2. The change does not impact the sterilization procedure of a sterile drug product.

Supporting data

1. Package Insert and Inner and Outer Labels, when applicable.
2. (P.2) Information demonstrating suitability of the proposed container/closure system for its intended use (evidence that it is meeting the relevant pharmacopoeial tests, such as:
   • USP <661> Plastic Packaging Systems and their materials of construction
   • USP <1663> and <1664> Extractables and Leachables
   • USP <87> Biological Reactivity Tests, In Vitro
   • USP <88> Biological Reactivity Tests, In Vivo, as applicable
   • USP <381> Elastomeric Closures for Injection
   • USP <671> Containers - Performance Testing
   • Description of any additional treatments such as sterilization and depyrogenation of the components
3. (P.3.5) For sterile products, process validation and/or evaluation studies.
4. (P.7) Information on the proposed container closure system (such as description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate).
5. (P.8.1) Stability Summary and Conclusions; results of a minimum of 2 pilot scale batches, 3 months of accelerated (or intermediate as appropriate) and 3 months of long-term testing and, where applicable, results of photostability studies.
6. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long-term stability program (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).

38. Change in the specification for a primary or functional secondary container closure component

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in the specification for a primary or functional secondary container closure component, involving deletion, replacement or addition of a test or; relaxation or tightening of an acceptance criterion	None	1,2	Notifiable Change
	1,2	1,2	Annual Notification

Conditions

1. The deleted test has been demonstrated to be redundant with respect to the remaining tests.
2. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.

Supporting data

1. (P.7) Updated QC approved proposed specifications, including justification.
2. (P.7) Description of the analytical procedure and, if applicable, validation data.

3.2.P.8 Stability

39. Change in the shelf-life for the drug product

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 product meets the approved stability specification.
2. Full long-term stability data is available covering the proposed shelf-life and is based on stability data generated on at least 3 commercial scale batches.

Supporting data

1. (P.8.1) Summary of stability testing and results (such as studies conducted, protocols used, results obtained).
2. (P.8.1) Proposed storage conditions and shelf-life.
3. (P.8.2) Updated post-approval stability protocol and stability commitment.
4. (P.8.3) Results of stability testing (full long-term stability data covering the proposed shelf-life generated on at least 3 commercial scale batches of each strength for each approved packaging format/size), if applicable. Bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified.

40. Change in the product in-use stability period

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Extension or addition	1	1,2	Notifiable Change

Conditions

1. No change to the container closure system.

Supporting data

1. Package insert, Inner and Outer Labels
2. Results of in-use stability tests that simulates the condition of use and lasts the duration of the intended in-use stability period. Tests results should be provided for physical, chemical and microbial properties of the product. The analytical procedures used in the studies should be described and fully validated and a minimum of 2 pilot scale batches should be used in the study. One of the batches should be approaching the end of its shelf life.

41. Change in the storage conditions for the drug product or the diluted or reconstituted product

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition of a cautionary statement	1	1,2	Annual Notification
Deletion of a cautionary statement	None	1,2	Notifiable Change
Relaxation of a temperature criterion	None	1,2	Notifiable Change
Tightening of a temperature criterion	1	1,2	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.

Supporting Data

1. Package Insert and Inner and Outer Labels.
2. (P.8.3) If applicable, stability testing results to support the change to the storage conditions.

42. Change to the post-approval stability protocol for commitment or ongoing batches

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition of a time point at any time, or deletion of time points beyond the approved shelf-life	1	1-4	Annual Notification
Changes to comply with a relevant VICH guidance (such as deletion of a time point from previously approved stability protocol, or change in storage conditions)	1	1-5	Annual Notification

Conditions

1. No significant changes to the stability data (as defined in VICH GL 3: "Stability Testing of New veterinary Drug Substances and Medicinal Products" and VICH GL 8: "Stability Testing for Medicated Premixes").

Supporting Data

1. (P.8.1) Summary of stability testing and results (such as studies conducted, protocols used, results obtained).
2. (P.8.1) Proposed storage conditions and shelf-life.
3. (P.8.2) Updated post-approval stability protocol and stability commitment.
4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
5. (P.8.3) Results of stability testing (full long-term stability data covering the proposed shelf-life generated on at least 3 commercial scale batches, bracketing and matrixing could be applied, if justified).

3.2.R.2 Devices

43. Change of an approved device used for administration of a veterinary drug

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Addition or replacement of a drug administration device that is not an integrated part of the primary packaging of a veterinary drug product	3,6	1-3,6	Notifiable Change
	1-6	1,3,6	Annual Notification
Deletion of a drug administration device that is not an integrated part of the primary packaging of a veterinary drug product	3	1,3,6	Annual Notification
Change in an approved multi-dose administration device for an injectable veterinary drug product	4	1-6	Annual Notification

Conditions

1. No change in the type of drug administration device or materials of construction.
2. No change in the function, suitability, and accuracy of the device.
3. The required dose of the veterinary drug product must still be accurately delivered in line with the approved posology and the results of such studies should be available.
4. The change should be consistent with the posology and treatment duration.
5. The change does not concern a sterile drug product.
6. No change in the strength, pharmaceutical form, or route of administration of the drug product

Supporting data

1. Package Insert and Inner and Outer Labels, when applicable.
2. Data demonstrating the suitability and compatibility of the materials of construction of the device system (such as extractable/leachable testing, permeation testing, biological reactivity tests light transmission, as applicable).
3. Information on the proposed measuring device system (such as description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate).
4. (P.8.1) Stability summary for a moderate change to the drug administration device system (such as different materials of construction); where applicable, in-use stability studies for multi-dose veterinary drugs.
5. (P.8.2) Updated post-approval stability protocol.
6. Reference to certificate of analysis, or other manufacturer standards for the device, where applicable, demonstrating the delivered dose (accuracy, precision) of the proposed device.

44.Change to a device used for the administration of an extended release veterinary drug

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change to a device used for the administration of an extended release veterinary drug [such as addition, deletion, replacement of, or change in materials of construction of an extended release device (such as for intraruminal boluses used for continued release) of a veterinary drug product].	None	1-7	Supplement
	3-5	1,3-7	Notifiable Change
	1-6	1,3-7	Annual Notification

Conditions

1. No change in the type of or materials of construction (such as composition of glass bolus).
2. No change in the shape or dimensions, function, suitability, and accuracy
3. The required dose of the veterinary drug product must still be accurately delivered in line with the approved posology and the results of such studies should be available.
4. The change should be consistent with the posology and treatment duration.
5. No change in release of the drug product into the digestive system and no impact on bioavailability of the active medicinal ingredient.
6. The new device is free from BSE / TSE agent (such as encapsulated gelatin).

Supporting data

1. Package Insert and Inner and Outer Labels, when applicable.
2. (1, 5) Supporting clinical or comparative dose delivery data, where applicable.
3. Data demonstrating the suitability of the materials of construction of the device system (such as extractable/leachable testing, permeation testing, biological reactivity tests, light transmission, as applicable). For changes to dose administering device, data to demonstrate that the delivered dose with the new device is equivalent to that previously approved.
4. (P.7) Information on the proposed dose delivery system (such as description, materials of construction of components, specifications, including results of transportation studies, if appropriate).
5. (P.8.1) Stability Summary and Conclusions, where applicable, results of in-use stability studies for multi-dose veterinary drugs.
6. Reference to certificate of analysis, or other manufacturer standards for the device, where applicable, or data to demonstrate accuracy, precision and compatibility of the device.
7. TSE Certificate of Suitability (CEP) issued by the EDQM, if available, or satisfactory TSE risk assessment on material of construction of the device.

45. Minor changes to a device used for the administration of an extended release veterinary drug

Description of change	Conditions to be fulfilled	Supporting data	Reporting category
Change in specification limits of an administration device for a veterinary drug (such as changes in balling gun used for intraruminal boluses to control drug product rate of release).	None	1-4	Notifiable Change
	1	1,4,5	Annual Notification
Minor change to an approved test procedure	1	3-5	Annual Notification
Addition of a new test parameter	None	1,4	Annual Notification

Conditions

1. Any change should be within the range of currently approved limits.

Supporting data

1. Package Insert and Inner and Outer Labels, when applicable.
2. Data demonstrating the suitability of the materials of construction of the measuring device system [such as extractable/leachable testing, permeation testing, biological reactivity tests, light transmission, as applicable]. For changes to measuring device, data to demonstrate that the measuring of the new device is equivalent to that previously approved.
3. (P.3.5) For sterile products, process validation data and/or evaluation studies, where applicable.
4. (P.7) Information on the proposed dose delivery system [such as description, materials of construction of components, specifications, including results of transportation or interaction studies, if appropriate; detailed description, drawing and composition of the device material and manufacturer specification].
5. Reference to certificate of analysis, or other manufacturer standards for device, where applicable, or data to demonstrate accuracy, precision and compatibility of the device.