post-noc changes

Post NOC Changes

Our Team Arya Yogender

Maryam Tabatabaei

Neha Gandhi

Shabnam Noushin

Professional Regulatory Affairs, Course Code: PRA 1008/1009, Sept. 2012 Academy of Applied Pharmaceutical Sciences, Toronto, Canada

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Content

• Introduction

• Guidance of Implementation

• Quality Document- Documentation

• Examples

• References


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Introduction These Post NOC changes can happen for the following reasons

- To improve the quality of the drug. - To improve the efficiency of manufacturing process. - To solve the marketing issues. - Changes in labeling of the drug for “warning” or managing the “risk factors” or limiting the “targeted population” or limiting the “dosage”.

These drugs may include pharmaceuticals, biologics, and radiopharmaceuticals for human use and pharmaceutical, radiopharmaceutical and certain biotechnological products for veterinary use


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Introduction Policy Statement

Health Canada recognizes that: - any change to a drug may impact the safety, efficacy and quality of that drug and; - any change to the information associated with the drug (for example [e.g.], labeling)may impact the safe and effective use of that drug. To manage the safety and risks of the public in using the drugs and foods, there are certain rules and regulations administered by “Health Canada”. One important area of these regulations are administrative rules managing the “Post Notice of Compliance” ( Post NOC )related to a drug.

A post-NOC change is any change that is made to a new drug that has received a NOC pursuant to section C.08.004 of the Food and Drug Regulations.


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Introduction “Post NOC” changes applies

- When a drug has already been granted a “ NOC” ( Notice of Compliance) - When a drug is recommended for NOC ( Notice Of Compliance ) but this notice is on hold.

These drugs may include pharmaceuticals, biologics, and radiopharmaceuticals for human use and pharmaceutical, radiopharmaceutical and certain biotechnological products for veterinary use


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Introduction Objectives and Goals of these regulations

- providing a frame to define what is meant by significantly different as it relates to preventing the sales of the drug to the public (Section C.08.003 ). - providing sponsors with recommendations on the data required to enable Health Canada to make an accurate determination of the impact of a change on the safety, efficacy and quality of the new drug.


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Introduction Level of changes to a drug and subsequent obligations of the sponsor are as followings Levels

- Supplements. (Data should be submitted to Health Canada for review prior to implementation. ) - Notifiable Changes. (Data should be submitted to Health Canada for review prior to implementation.) - Annual Notifications. (Data should not be submitted but should be available to health Canada upon request ) - Record Of Changes.(Data should be retained by sponsor )


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Introduction As of the effective date, the Post-NOC Changes guidance documents will supersede the following guidance and policies

a) New Drug: Sufficient Time policy (1991) b) Extension of Expiration Dates (1991) c) Changes to Marketed New Drug Products policy (1994) d) Stability Requirements for Changes to Marketed New Drugs (1994) e) Changes in Product-Specific Facility Information (revised in 2004) f) New Drug: Sufficient Time notice (2005) g) Draft Guidance for Industry: Changes in Product Colours or Markings (2005)


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Frame-work Document This Framework document and the associated Post-NOC Changes guidances came into effect on 30th September 2009.

Health Canada recognizes that changes allowed under the New Drug: Sufficient Time policy (1991) were not required to be reported. Therefore sponsors are reminded that changes previously implemented under the New Drug: Sufficient Time policy need not be reported at this time.

All changes from the effective date of the Post-NOC Changes guidances are expected to be reported as per the procedures detailed within.


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Guidance for implementation Reporting Categories

Level I – Supplements

These changes to a new drug are “significantly different” as it relates to the matters specified in C.08.003 (2) of the Food and Drug Regulations and have the potential to impact the safety, efficacy, quality and/or effective use of the drug. The changes included in this reporting category shall be filed, along with the recommended supporting data, to Health Canada as a Supplemental New Drug Submission (SNDS) or Supplemental Abbreviated New Drug Submission (SANDS).

The change may not be implemented by the sponsor until a NOC has been issued!


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Level II - Notifiable Changes

These changes to a new drug have the potential to impact the safety, efficacy, quality and/or effective use of the drug but do not require the issuance of a NOC. (NOTE: All Level II - Notifiable Changes (Quality) referred to in this document are not applicable to Human

Pharmaceuticals)

The changes included in this reporting category should be filed, along with the recommended supporting data, to Health Canada as a Notifiable Change.

All Level II changes should not be implemented by the sponsor until a No Objection Letter (NOL) has been issued!


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Level III - Annual Notifications

These changes to a new drug have minimal potential to impact the safety, efficacy, quality and/or effective use of the drug. The changes included in this reporting category may be implemented by the sponsor without the prior review by Health Canada of the data supporting such a change. These changes should be annotated in the affected documents when filing the next submission to Health Canada to indicate those Level III changes that have been implemented.

The recommended supporting data should not be submitted but should be available to Health Canada within thirty (30) calendar days if requested at any time!


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Level IV - Record of Changes (Quality only)

These changes to a new drug are not Level I, Level II or Level III and are not expected to impact the safety, efficacy, quality and/or effective use of the drug. The changes

included in this reporting category may be implemented by the sponsor without prior review by Health Canada.

The changes should be retained as part of the drug product’s record by either the sponsor or the manufacturer and comply with Good Manufacturing Practices (GMP) requirements of Division 2 of the Food and Drug Regulations!


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Guidance for implementation Pre-Submission Enquiries

When in doubt as to the classification or supporting documentation, sponsors are encouraged to contact Health Canada in writing for clarification. Verbal enquiries should be followed-up in writing by the sponsor!

Health Canada will provide a written response within fifteen (15) calendar days of a pre-submission enquiry.


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Guidance for implementation Submission Filing

Sponsors are requested to send their information and material to the Submission and Information Policy Division (SIPD) at the following address:

Submission and Information Policy Division Therapeutic Products Directorate Finance Building # 2 Tunney’s Pasture, A.L. #0201A1 Ottawa, ON K1A 0K9 Fax: (613) 941-0825


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Submission Filing Items to be Included in the Submission:

Level I and Level II Changes

- The completed documents: Drug Submission Application Form (Health Canada 3011) signed and dated

Drug Submission Fee Application Form

Submission Certification Form - signed and dated

Letter of Attestation for submissions filed in electronic Common Technical Document (eCTD) format –

signed and dated

- Patent information pursuant to the Patented Medicines (Notice of Compliance) Regulations - Good Manufacturing Practices (GMP) and Establishment Licensing (EL) Information - Letters of Access for any supporting Drug Master Files and Site Reference - An annotated and non-annotated electronic and an annotated hard copy of:

the Certified Product Information Document (CPID); and

the Product Monograph or Package Insert (for Veterinary drugs)

- A sample of the inner and outer labels.


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Submission Filing Items to be Included in the Submission:

Level I and Level II Changes

A covering letter that includes: the type of submission (i.e. SNDS, SANDS or NC) a narrative of the change(s) and a brief rationale for the change(s) any other information relevant to the submission an indication of the general type of supporting data for submissions filed in the electronic Common Technical Document - eCTD format, include a description of the electronic submission including type and number of electronic media, approximate size of the submission, a statement that the submission is virus free with a description of the software used to check the files for viruses, and the regulatory and eCTD points of contact for the

submission


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Submission Filing Level III - Annual Notifications

The following items should be included, where applicable, with the sponsor’s Annual Drug Notification: - A listing of all Level III changes for each new drug that has received a NOC and that have occurred in the preceding twelve (12) months compiled using the Level III form or format - A copy of the most recent revised label(s) (inner and outer) if a Level III label change has been made

Note: Supporting data for the Level III changes recommended in the associated guidance documents should not be submitted with the Annual Drug Notification; however, the data should be available to Health Canada within thirty (30) calendar days if requested at any time.


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Submission Filing Level IV- Record of Changes

These changes should be retained as part of the drug product’s record by either the sponsor or the manufacturer and comply with Good Manufacturing Practices (GMP) requirements of Division 2 of the Food and Drug Regulations.

These changes should be annotated in the affected documents with the filing of the next submission to Health Canada.


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Post NOC Changes- Quality Document General Information: There are Appendix 1 (Human Pharmaceutical),Appendix I (Veterinary Pharmaceuticals), Appendix 2 (Veterinary Drugs), Appendix 3 (biologics), and Appendix 4 (Schedule C Drugs) to assist with the classification of changes made to the Quality information. The information summarized in the tables provides recommendations for: conditions to be fulfilled, supporting data and reporting category


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Quality Document Supporting Data- Level I and Level II Changes

-All data recommended to support the change should be provided with the submission - Where applicable, data should be provided in the format defined by the International conference of Harmonization (ICH) Common Technical Document (CTD). For Veterinary Drug Submissions, data should be provided in the format of the Guidance for Industry: Preparation of Veterinary New Drug Submissions. -A Quality Overall Summary (QOS) and Comprehensive Summary: Bioequivalence (CS:BE) should also be completed and provided


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Quality Document Production documents (Executed and Master Batch Records)

For Biologics and Radiopharmaceuticals, in contrast of the requirement for a NDS, production documents are no longer required at time of filling to support any Post-NOC. However, these may be requested during review and should be available within 15 days upon request

Consistency lot testing

-Is for Biologics (Schedule D Drugs) and Radiopharmaceuticals (Schedule C drugs), Level I and Level II changes. - It should come from three to five consecutively manufactures lots -Sponsors are encouraged to consult the Health Canada guidance document “ Lot release program for Schedule D (Biologic)drugs” for further guidance


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Quality Document On-Site Evaluation (OSE)

-It is for Biologics and Radiopharmaceuticals -Sponsors are encouraged to discuss OSE requirement prior to submission changes

Certificate of Suitability (CEP)

- Issued by European Directorate for the Quality of Medicines of the Council of Europe (EDQM) in support of changes to drug substance -Not applicable for Biologics (Schedule D Drugs) -Is under review in pharmaceuticals for use in human (Appendix I- Human Pharmaceuticals) - Transmissible Spongiform Encephalopathy (TSE)-CEP may be provided to support raw material, auxiliary materials and reagents at risk of transmitting BSE/TSE agents for Biologics


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Quality Document Comparative Studies

Comparative In vivo Studies A number of changes outlined in Appendices 1, 2, 3 and 4 include recommendations for supporting comparative in vivo studies (e.g. comparative bioavailability studies for Pharmaceuticals, bridging clinical studies for Biologics)

Comparative In Vitro Studies A number of changes outlined in Appendices 1, 2, 3 and 4 include recommendations for supporting comparative in vitro studies (e.g. Comparative dissolution studies) Appendix 5 outlines a number of recommendations for conducting and assessing comparative dissolution profiles.


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Quality Document

Stability Testing

- If stability studies are recommended to support a change, these studies should be conducted in accordance with applicable ICH and Health Canada documents - In case where accelerated stability studies are not routinely performed due to the nature of the product, a rational should be provided.


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Pharmaceutical Development and Quality by Design -ICH has develop guidelines, Q8: Pharmaceutical development and Q8 Annex - Health Canada is in the process of adopting ICH Q8 and Q8 Annex - Provides scientific understanding to support the establishment of the design space, specifications and manufacturing controls - Working within design space is not considered as a change that would require prior approval !! But should be documented with the requisite Change Controls where necessary -For example, some of the Post-NOC changes that are listed in Appendices 1,2,3, and 4 as level I or Level II may not require approval prior to implementation if they are within the approved design space -Movement outside of the design space is considered to be a change - For existing products establishing a new design space is possible


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Post NOC Changes- Example Level I changes

1. Any change to the existing text of the labels (including Package Insert5 or Part III of the Product Monograph) that refers to any potential benefits of the drug, implicit or explicit, including claims regarding the safety profile or efficacy. This includes changes in text with reference to sub-populations and species (for veterinary drugs), and any reference to possible claims regarding side effects.

2. A new indication has been added, including reintroduction of an indication that had received a Notice of Compliance and was subsequently withdrawn, or the existing text of an indication has been revised (other than changes to improve risk management as per Level II (90 day) Risk Management criteria).


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Post NOC Changes- Example Level II changes

1. Addition to, strengthening or clarification of text anywhere in the sections: CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS (CAUTIONS for veterinary drugs) and ADVERSE EVENTS of the Package Insert or Part I or III of the Product Monograph, including changes as a result of an advisory. These changes may include the provision of recommended risk-management actions (e.g., required testing prior to initiation of the drug, specific monitoring during product use, ensuring patient awareness of certain risks, etc.), or the identification of a specific sub-population as being at greater risk such as those with a concomitant condition, those taking concomitant medicine, or a specific age group.

2. The instructions for use including dosage and administration, anywhere in the Package Insert or Part I or Part III of the Product Monograph, have been reworded and/or otherwise altered with respect to optimizing the safe use of the drug.


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Post NOC Changes- Example Level III changes

1. Any change to the layout of the label that does not represent a change to the labeling requirement of Sections C.01.004 and A.01.016 of the Food and Drug Regulations (e.g., contrast, artwork, font, position) or the terms of market authorization.

2. Changing a publication in the REFERENCE section of the Product Monograph/Package Insert listed as “in press” to a published listing.


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References


1- Health Canada, Post-Notice of Compliance (NOC) Changes: Framework Document , 2009 (Online), Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/postnoc_change_apresac/noc_pn_framework_ac_sa_cadre-eng.php [Accessed on Sept. 1, 2012) 2- Health Canada, Post-Notice of Compliance (NOC) Changes: Quality Document, 2011 (Online), Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/postnoc_change_apresac/noc_pn_quality_ac_sa_qualite-eng.php [Accessed on Sept. 1, 2012)

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http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/postnoc_change_apresac/noc_pn_framework_ac_sa_cadre-eng.php











http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/postnoc_change_apresac/noc_pn_quality_ac_sa_qualite-eng.php











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