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: bgtd_ora@hc-sc.gc.ca)

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: del_questions_leppp@hc-sc.gc.ca

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!!!