Regulatory Expectations for Method Transfers:
Health Canada's Perspective
CMC Strategy Forum – Methods on the move
January 23, 2017
Hugo Hamel, Senior Biologist/Evaluator, BGTD
Overview of the Post-NOC Changes Quality
Guidance (PNOCC) • Scope & Application
• Structure
• Reporting categories
Regulatory expectations for method transfers• Pharmacopoeial vs non pharmacopoeial
• Same building, different rooms
• Different building, same licence number (DEL#)
• Different building, different licence number
Examples of issues with method transfers
Outline
PNOCC guidance documents originally posted in September, 2009
– Framework document
– Safety & Efficacy (S&E) document
– Quality document
Revised in 2013 and 2016
– Based on the experience from the industry and BGTD
– Addition of new example of changes
– Increased clarity (correction of the conditions and supporting data)
Post-NOC Changes Quality Guidance (PNOCC) –
Overview
To assist with the classification of quality changes made to
a new drug that has received a Notice of Compliance
(NOC).
To provide sponsors with recommendations on the
minimum data to support a change which would be
considered sufficient to allow a determination of the impact
of the change on the quality of the new drug as it relates to
safety, efficacy and/or effective use of the new drug.
PNOCC Quality guidance document – Objectives
This guidance document applies to sponsors intending to
make changes to new drugs that have received a NOC
pursuant to Section C.08.004 of the Food and Drug
Regulations.
This guidance applies to the following products:
Pharmaceuticals
Veterinary drugs
Biologics
Radiopharmaceuticals
PNOCC Quality guidance document –
Scope & Application
Introduction
Appendix 1: post-NOC changes (Pharmaceuticals)
Appendix 2: post-NOC changes (Veterinary Drugs)
Appendix 3: post-NOC changes (Biologics)
Appendix 4: post-NOC changes (Schedule C drugs)
Appendix 5: Recommendation for comparative Dissolution
profile
Appendix 6: Changes to Excipients
Appendix 7: Examples of Level IV Changes
Appendix 8: Glossary
Structure of the Quality guidance
Quality changes are assessed based on their potential to have
an adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.
Level I – Supplements (Major Quality Changes)
Level II – Notifiable Changes (Moderate Quality Changes)
Level III – Annual Notification (Minor Quality Changes)
Level IV – Record of Changes (Changes with no impact)
PNOCC Quality guidance document –
Reporting Categories
Comparative table on how post-approval
changes are regulated among major NRAs
Conditions:
– All conditions must be met in order to file the change at the
proposed Level of filing
– If any of the conditions outlined for a given change are not
fulfilled, the change is considered at the next higher level
Supporting data:
– Detailed rationale must be provided when recommended
supporting data cannot be provided
PNOCC Quality guidance document –
Risk-based approach
Transfer of QC testing activities – Drug Substance
Facility : A building in which a specific manufacturing
operation or multiple operations take place.
Transfer of QC testing activities – Drug Product
Facility : A building in which a specific manufacturing
operation or multiple operations take place.
Introduction of additional laboratory facility in a facility to perform
drug substance or drug product testing.
For biologics and radiopharmaceuticals, with the exception of a
potency assay or a bioassay, transfer of the QC testing
responsibilities for a pharmacopoeial assay to a different facility
within the same company.
For biologics and radiopharmaceuticals, with the exception of a
potency assay or a bioassay, transfer of the QC testing
responsibilities for a pharmacopoeial assay to a different
company listed on the sponsor’s establishment licence.
Appendix 7: Examples of Level IV changes (on-site
records)
Filing requirements for the following method transfer
scenarios
Contact the Office of Regulatory Affairs (ORA) to discuss your situation
(E-mail: [email protected])
Potential paths:
• Written comments
• Teleconference
• Face-to-face meeting
DEL: Drug Establishment Licence
(S.2.5/P.3.5) Information demonstrating technology transfer qualification
The purpose is to ensure that the receiving laboratory is capable to perform a
particular analytical test that has been developed in another laboratory
The extent of data required to demonstrate technology transfer qualification
depends on different factors:
Whether the methods are pharmacopoeial or non-pharmacopoeial
Relative complexity of the assay (protein concentration vs HPLC vs Potency)
Difficulty of assay transfer
Whether same or similar equipment is used
− If different equipment is used, revalidation may be required
Whether changes have been made to the test procedures
Change in formulation (different excipients)
Risk assessment tools may be used to determine the potential risk associated
with the moving of the analytical methods to another lab (ICH Q9).
Technical transfer only
Partial or full revalidation
Supporting data recommended for the different method
transfer scenarios
Different approaches may be considered acceptable if scientifically
justified.
In general, the expectation is that concurrent testing at the donor and
receiving sites be performed to demonstrate that similar/comparable
results are obtained:
The acceptance criteria by which the receiving laboratory is deemed to be
qualified to use the methods being transferred should be clearly described in
the transfer protocol.
− Should include defined ranges of linearity, accuracy and precision (repeatability)
Adequate statistical analysis should be used to compare the means and the
variability of the results at both sites.
3 batches (in triplicate) with quantifiable amount of impurities should be tested.
If not the same, samples should be of similar age, have same homogeneity and
stored in the same container closure system and storage condition (should be
clearly indicated)
Spiked samples should be used when samples do not contain impurities above
LOQ
Supporting data recommended for the different method
transfer scenarios (cont’d)
Evidence that the new company/facility is GMP compliant
The new testing facility should have current evidence of GMP compliance
GMP evidence must be based on inspection by Health Canada or a trusted
regulatory partner (MRA, PIC/S, EDQM, WHO, others who inspect against
ICH Q7 Guidelines)
The Regulatory Operations and Regions Branch (RORB) of Health Canada is
the organization responsible for performing inspection and for issuing evidence
of GMP compliance.
A drug tested at the new site cannot be released in Canada until the new
testing site is listed on the sponsor’s Establishment Licence.
The RORB is also the organization responsible for performing Drug
Establishment Licencing
The timeline for processing amendment request is 250 calendar days.
− Drug Establishment Licences
E-mail: [email protected]
Supporting data recommended for the different method
transfer scenarios (cont’d)
Defined in a guidance document
Guidance documents are administrative instruments not having force of
law and, as such, allow for flexibility in approach.
Alternate approaches to the principles and practices described in the
guidance document may be acceptable provided they are supported by
adequate justification.
Supporting data are required for Level 2 and Level 3 changes
Must be provided only for Level 2 changes (Notifiable Change)
Must be provided upon request for Level 3 changes (Annual Notification)
Supporting data recommended for the different method
transfer scenarios (cont’d)
1. No concurrent testing was performed:
– Transfer of a potency assay for a new strength to a company approved for the
original strength
– Original technical transfer data were provided in support of the transfer of the
potency assay for the new strength
– When results from concurrent testing were requested, the data showed that the
potency results were systematically different at the new site
2. Lack of details in the transfer protocol with respect to sample preparation,
equipment setting and technical operations
– Transfer of HPLC quantity assay
– Variance in results between labs, day-to-day and analyst-to-analyst was
observed
– Lack of details regarding sample preparation
– Different devices were used for reconstitution, which resulted in difference in
amount of diluent added and thereby, resulting in differences in concentration.
Examples of issues with method transfers
3. Lack of suitable acceptance criteria relevant to the tests
– For simple assay (e.g. protein concentration by UV), the acceptance criteria
are based on the release specifications (+/- 10%), which is considered too
wide to demonstrate comparability.
– For moderately complex assay (e.g. HPLC), the acceptance criteria for the
difference between the mean and for the intermediate precision should not be
too wide
Examples of issues with method transfers (cont’d)
Suitable acceptance criteria are critical element of the method transfer
• Criteria that are too tight could lead to rejection of acceptable results
• With criteria that are too loose, the receiving laboratory could pass the
transfer but be unable to appropriately test the products
Purpose of the technical transfer activities is to maintain the validated state
of the method at the receiving site.
Regulatory expectations with respect to method transfer are defined in the
post-NOC changes quality guidance document.
Transfer of non-pharmacopoeial methods must be pre-approved (requires
the filing of a Level 2 – Notifiable Change) except for a transfer in the same
building, different room.
Transfer of pharmacopoeial methods can be implemented without prior
approval (Level 3 or Level 4 changes).
In term of supporting data, the fact that the requirements are defined in a
guidance document provides some flexibility. Different approaches may be
considered acceptable if scientifically justified.
Appropriate statistical analysis should be performed to demonstrate
equivalence of the data set at the sending and receiving sites.
Contact the Office of Regulatory Affairs to discuss your situation.
Conclusion
Thank You!!!
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