tpd quality guidances and the new qos-ce templates
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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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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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Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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”
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Be Consistent with ICH's CTD-Q / Question & Answer Document
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Be Consistent with ICH's CTD-Q / Question & Answer Document
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Address Concerns over Proprietary Software Specifications
Drum roll, please...
‘WORD’
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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).
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Highlights of Specific Templates
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Highlights of Specific Templates
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.
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Highlights of Specific Templates
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)
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Highlights of Specific Templates
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Highlights of Specific Templates
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)’
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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.
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Points to Consider / Tips
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Points to Consider / Tips
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Points to Consider / Tips
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Points to Consider / Tips
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.
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
ICH Quality Guidelines
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
Date Reached Step 4 at ICH(date adopted by HC)
ICH Quality Guideline
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
ICH Quality Guidelines
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
Date Reached Step 4 at ICH(date adopted by HC)
ICH Quality Guideline
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
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.
Health SantéCanada Canada
Health Products and Food BranchDirection générale des produits de santé et des aliments
Thanks,Arvin NaperstkowActing Senior Scientific Advisor - Quality,Bureau of Pharmaceutical Sciences,TPD, Health Canadaarvin_naperstkow@hc-sc.gc.ca
Gary CondranActing Senior Scientific Advisor - Policy,Bureau of Pharmaceutical Sciences,TPD, Health Canadagary_condran@hc-sc.gc.ca
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