TPD Quality Guidances and the New QOS-CE Templates

Health SantéCanada Canada

Health Products and Food BranchDirection générale des produits de santé et des aliments

TPD Quality Guidances andthe New QOS-CE Templates

Arvin Naperstkow, M. Sc.,Acting Senior Scientific Advisor - Quality,Bureau of Pharmaceutical Sciences,Therapeutic Products Directorate, Health Canada

CAPRA CTD/eCTD WorkshopMontréal, June 1-2, 2004



Outline

CTD-Q:• Module 3.2 – Quality Module• Module 2.3 – Quality Overall Summary (QOS)

Tips for Preparing Information• Module 1 – Admin. / Prescribing Information

Related TPD/ICH Quality Guidance Documents

CTD-Q Implementation

Module 1Regional

AdministrativeInformation

QUALITYOVERALL

SUMMARY 2.3

NonclinicalOverview

2.4

ClinicalOverview

2.5

NonclinicalSummaries

2.6

ClinicalSummary

2.7

MODULE 3

QUALITY

Module 4

NonclinicalStudy Reports

Module 5

Clinical Study Reports

Module 2

Not Partof CTD

CTD

Application

Applicationin CTD Format

CTD Table of Contents 2.1

CTD Introduction 2.2



Common Technical Document - Quality

Purpose:• provides guidance on where information is to be placed, not whatshould be filed ... ICH and domestic guidance documents continue to describe content requirements

Scope:• as defined by the ICH guidelines “Q6A” (New Chemical Entities) and “Q6B” (Biotech. Products)• in Canada, the CTD/CTD-Q format has been extended to other types of applications, e.g.,

• Clinical Trial Applications (CTAs), Abbreviated New Drug Submissions (ANDSs), Applications for DINs (DINAs), Drug Master Files (DMFs) (provided the “Open” and “Closed” portions of the Type 1 DMFs are submitted), applications for post-approval changes



Module 3 – Quality

3.1 Table of Contents of Module 3

3.2 Body of Data• 3.2.S Drug Substance• 3.2.P Drug Product• 3.2.A Appendices• 3.2.R Regional Information

3.3 Literature References

CTD-Quality Scenarios

MODULE 3: QUALITY

3.2 Body ofData 3.3 Literature

References3.1 Table ofContents ofModule 3

3.2.R RegionalInformation

3.2.S DrugSubstance

(name, Mnf.)

3.2.P DrugProduct

(name, dosageform)

3.2.A Appendices

3.2.S DrugSubstance

(Name X, Mfr. A)3.2.S Drug

Substance (Name Y)3.2.P Drug Product(Name X, Tablets)

3.2.P Drug Product(Name X,Parenteral)

Manufacturer B Manufacturer C Strengths(10, 50, 100 mg)

Bottles(25, 50, 1000 tabs) Unit Dose Blisters

3.2.P Drug Product(Name X, Diluent)

Com

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to a

ll A

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Module 2.3 - What is a “QOS”?

A Quality Overall Summary (QOS):• is part of a drug submission organized according to ICH’s CTD format• represents a summary that follows the scope and the outline of the Quality Body of Data (Module 3.2)• should not include information, data or justification that was not already included in Module 3 or in other parts of the CTD• in Canada, has been extended to other types of applications:

e.g., CTAs, ANDSs, DINAs, DMFs (provided the ‘Open’ and ‘Closed’ portions of Type 1 DMFs are submitted), and applications post-approval changes



What is a “QOS-CE Template”?

A Quality Overall Summary – Chemical Entities (QOS-CE) Template:

• is a template made available for sponsors to assist in the preparation of the QOS • is entirely compatible with ICH’s QOS• can be considered an acceptable replacement for the QOS as defined by the CTD-Q guidance • promotes review efficiencies by serving as the basis for the Quality assessment report• provides additional guidance with respect to technical content requirements• is encouraged, but not mandatory



Summary of Updates

The QOS-CE templates have been updated to:• be consistent with ICH's CTD-Q (e.g., notably the release of the Step 4 ‘ Questions and Answers’ document)• reflect revisions as a result of comments received during the Stakeholder consultation period, where appropriate• streamline their structure• address concerns over proprietary software specifications• be available in both official languages



Be Consistent with ICH's CTD-Q / Question & Answer Document

The CTD was re-issued by ICH in 2002 for consistency and use with the eCTD (included granularity document, definition of a ‘document’):

• CTD-Q clarifications2.3.S Drug Substance (name, manufacturer)2.3.P Drug Product (name, dosage form)

Appendix 1 – Facilities and Equipment• originally believed to be applicable for Biotech. products only• however, upon clarification ... could also apply to “Chemical Entities”




CTD-Q/Q&A Document in 2003:• multiple references in different sections (e.g., Polymorphism, Particle Size, Impurities)• S.1.3 General Properties – only the proposed polymorphic form• S.3.1 Elucidation of Structure and other Characteristics –results of studies on potential polymorphic forms, to identify the PSD• S.4.4 Batch Analyses – summary of historical analytical procedures• S.7.3 Stability Data – summary of analytical procedures used only for stability studies




CTD-Q/Q&A Document in 2003:• P.2.2.1 Formulation Dev. – summary of IVIVC studies (with cross-reference to Module 5)• P.2.2.1 Formulation Dev. – summary of studies on scored tablets• P.2.4 Container Closure System – info. on the performance of the C/C system (e.g., priming of MDIs)• P.4 Excipients – summary of data on a “significant amount of data” for noncompendial, nonnovel excipients should go in Appendix 3• P.8.1 Stability Summary – the Shelf-life specification should be provided



Reflect Comments Received /Streamline their Structure

Feedback from Stakeholder:• S.1.3 General Properties – less emphasis on dose/solubility volume (not applicable to all dosage forms)• clarify when BSE/TSE supporting information is necessary• most of the comments received impact the parent Quality guidance documents (Stay tuned)

Streamline their Structure:• significantly reduced the number of tables• essentially ‘no format’ ... free flowing text• Analytical Procedures and Validation tables are not part of the updated package



Address Concerns over Proprietary Software Specifications

Drum roll, please...

‘WORD’



Address Concerns over Proprietary Software Specifications

Now available in both Corel® WordPerfect and Microsoft® Word

Note: Sponsors are requested to submit original data files only in MS Word 2000 and above or in Corel WordPerfect versions 6, 7, 8, 9, or 10.

Use the appropriate template for the original word processing format of their choice (i.e., Word template for Word submissions and WordPerfect template for WordPerfect submissions).



Module 1 – Administrative Information and Prescribing Information

Quality information in Module 1:• 1.2.5 - GMP and Establishment Licensing (EL) Information• 1.2.6 - Letters of Access (e.g., allowing access to Drug Master Files)• 1.2.8 – Other Application Information (e.g., requests for waivers of Comparative Bioavailability Studies)• 1.3 – Product Labelling• 1.4.1 – Certified Product Information Document (CPID)

NDSs and ANDSs – provided upon requestSupplements and NCs – at the time of filing



Highlights of Specific Templates

QOS-CE (CTA – Phase I) and QOS-CE (CTA – Phase II/III):

• previous template has been split to avoid the repetitive “N/A for Phase I Studies” ... clarifies what is required at Phase I versus Phase II/III stages • clarifies that information should be provided “... on batches to be used in this clinical trial”• clarifies that if full long term stability data is not available, provide the stability protocol and a commitment for the continued monitoring of the drug product stability




QOS-CE (CTA – Phase I), important note...• the tables summarizing the drug substance and drug product specifications (Sections S.4.1 and P.5.1) were inadvertently removed from the ''QOS-CE (Phase I) template''• this will be rectified as soon as possible• until such time the updated template is available, sponsors should insert Sections S.4.1 and P.5.1 (e.g., summaries of the tests and methods) into the completed Quality Overall Summary for Phase I studies




QOS-CE (CTA – Phase BA):• received feedback from a number of Stakeholders (including CROs)• “Attestation that the drug substance was manufactured under GMP conditions”• Composition of the dosage form (complete either (i) or (ii)):

composition table or Attestation that the NMIs used in the formulation are

consistent with those found in the reference drug product ... or provide supporting documentation indicating the suitability of the ingredients.




QOS-CE (NDS/ANDS):• For raw materials from sources that are at risk of transmitting BSE/TSE agents (e.g., ruminant origin), a letter ofattestation (with supporting documentation) should be provided• Templates for “Summaries of Analytical Procedures and Validation Information” are not part of the updated package and are not required, however, a comparable level of information should be included in the QOS (e.g., summary of the various validation parameters and results of studies)




CPID-CE:• as the CPID-CE has an important role in the overall process (e.g., assessments of post-approval changes, Inspections, Provincial Formulary processes), its use will continue • should be included with NDSs and ANDSs (and subsequent changes) regardless of the format used for the QOS (i.e., either ICH QOS or HC QOS-CE)

Updates with CPID-CE:• P.3.4 - in-process controls for Drug Product• P.3.5 - summary of process validation protocol and/or studies




QOS-CE (DINA):• QOS should be provided at the time of filing for Group A DINAs (Schedule F drugs)• ref. ‘Quality Guidance: DINAs for Pharmaceuticals (draft, 2003)’



Points to Consider / Tips

Be “ACC”• Accurate / Consistent / Concise

If scanned images are incorporated into the document, ensure that a low resolution is used to avoid files that are excessively large…

• strive for a file of <2 megabytes• ~18 megabytes ... have mercy!!

It is understood that certain sections and fields may not apply and should be indicated by “N/A” with an accompanying explanatory note.




When summarizing analytical validation reports:• do not only use … “Methods have been fully validated according to ICH guidelines.”• also use … “The HPLC impurity method #XXX has been validated for the following parameters:

Accuracy: …Precision: …

When summarizing analytical results (e.g., stability data):

• discuss quantitatively• discuss trends/observations in data




Protocol for the Continuing Stability Progamme:• this is the protocol to be used for the batches added to the stability programme on an annual basis• not a protocol for the monitoring of batches that are currently enrolled in the stability programme




Tips:• S.2 Manufacture - cross-references to DMFs for proprietary information only ... info. from “Open DMF” should be included in the submission and summarized in the QOS• S.3.2 Impurities – include discussion why impurities identified in pharmacopoeial monograph are not tested (e.g., Ph.Eur. Transparent monograph)• P.7 Container Closure System – indicate material in direct contact with the drug product• P.8.1 Stability Summary – indicate the studies were performed in the packaging proposed for marketing




Tips:• P.3.3 Description of the Manufacturing Process –

indicate equipment type, working capacity, and process parameters

for sterile products – include details on the precise sterilization filters validated for this product (according to supplier, catalogue number, model number, pore size and materials of construction). In-process tests should specify the numerical integrity test limits for these filters. Sterilization conditions (temperatures, hold times) should be cited for all packaging components and manufacturing equipment.



ICH Quality Guidelines

2003(2003)

Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV

2003(2003)

Q1E: Evaluation for Stability Data

2002(2003)

Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products

1996(1998)

Q1C: Stability Testing: Requirements for New Dosage Forms

1996(1999)

Q1B: Stability Testing: Photostability Testing of New Drug Substances and Products

2003(2003)

Q1A(R2): Stability Testing of New Drug Substances and Products

Date Reached Step 4 at ICH(date adopted by HC)

ICH Quality Guideline




1997(1999)

Q3C: Residual Solvents

2003(2003)

Q3B(R): Impurities in New Drug Products

2002(in-process)

Q3C(M): Residual Solvents (revised limits for N-Methylpyrrolidone and Tetrahydrofuran)

2002(2003)

Q3A(R): Impurities in New Drug Substances

1996(1999)

Q2B: Validation of Analytical Procedures : Methodology

1994(1999)

Q2A: Text on Validation of Analytical Procedures






NewQ9: Risk Management

NewQ8: Pharmaceutical Development

2000(in process)

Q7A: Good Manufacturing Practices (GMPs) for Active Pharmaceutical Ingredients (APIs)

1999(in process)

Q6A: Specifications for New Drug Substances and New Drug Products: Chemical Substances





TPD Quality Guidance Documents

Quality Guidance: CTAs for Pharmaceuticals• draft – July 2001, finalized ... TBDQuality Guidance: NDSs and ANDSs for Pharmaceuticals• draft – July 2001, finalized ... TBDQuality Guidance: DINAs for Pharmaceuticals• draft – July 2003, finalized ... TBDThe above parent Quality guidance documents should be

read in conjunction with the preparation of the Quality Module and the QOS:

• a ‘Sample Completed QOS-CE’ is currently under development



CTD/CTD-Q Implementation

Need to integrate existing (and future) guidance documents into the CTD format

Need to consider ICH guidelines (and Regional guidelines from the ICH Parties) to ensure consistency or have valid reasons for differences:

• e.g., CTD-Q Questions and Answers Document, Quality guidance documents from FDA, EU, MHLW

Possible changes may be needed to Regulations to allow for adoption of some ICH guidelines:

• e.g., Q6A, Q7A



CTD/CTD-Q Implementation

QOS-CE Templates are now available:• can be used immediately or use can be phased in (sooner the better)• earlier versions of the templates would be accepted for those products currently under development• MS Word has been installed / some training completed

The implementation and use of the CTD represents a work in progress ... as such, it is expected that future refinements to guidance documents will continue to be necessary as a result of experiences gained.



Thanks,Arvin NaperstkowActing Senior Scientific Advisor - Quality,Bureau of Pharmaceutical Sciences,TPD, Health [email protected]

Gary CondranActing Senior Scientific Advisor - Policy,Bureau of Pharmaceutical Sciences,TPD, Health [email protected]