Post-NOC changes

Our Team
Arya Yogender

Maryam Tabatabaei

Neha Gandhi

Shabnam Noushin

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

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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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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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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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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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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