Lynda Paleshnuik | 4-5 April 20111 |
Meeting with Medicine Manufacturers
Geneva – 4-5 April 2011
Meeting with Medicine Manufacturers
Geneva – 4-5 April 2011
The New
Quality
Guideline
and
Templates
Lynda Paleshnuik
Lynda Paleshnuik | 4-5 April 20112 |
OverviewOverview
THE QUALITY GUIDELINE
� Background (PQP quality guidelines)
� Guideline development process
� Introduction to the two documents:
I: the preparation guideline
II: the quality guideline
� Key changes from the previous PQP quality guideline
� Navigating through the quality guideline
Lynda Paleshnuik | 4-5 April 20113 |
Overview ContinuedOverview Continued
THE QUALITY TEMPLATES
� Introduction to the two templates:
I: QOS-PD – quality overall summary - product dossier
II: QIS – quality information summary
� Uses/tips for QIS
Lynda Paleshnuik | 4-5 April 20114 |
New guidelinesNew guidelines
“Preparation” guideline: Guideline on submission of
documentation for a multisource (generic) finished
pharmaceutical product (FPP): Preparation of product dossiers
(PDs) in Common Technical Document (CTD) Format;
“Quality” guideline: Guideline on submission of
documentation for a multisource (generic) finished
pharmaceutical product (FPP): Quality part
Lynda Paleshnuik | 4-5 April 20115 |
BackgroundBackground
� Previous generic guideline: “Guideline on Submission of
Documentation for Prequalification of Multi-source (Generic)
Finished Pharmaceutical Products (FPPs) Used in the
Treatment of HIV/AIDS, Malaria and Tuberculosis” (2005)
� 2005-2011: policy/approaches to assessment change
continually over time due to harmonization efforts, scientific
advances, development of approaches
● e.g. process validation and pharmaceutical development
approaches have changed dramatically over the past 10 years
Lynda Paleshnuik | 4-5 April 20116 |
BackgroundBackground
ICH: International Conference on Harmonization
● joint regulatory-industry initiative to harmonise
regulatory requirements
● issued the Common Technical Document (CTD) -
Quality (ICH M4Q) guideline resulting in considerable
harmonization on the organization of the Quality
Module of the registration documents (= product
dossier)
● CTD format has become widely accepted by regulatory
authorities within and beyond the ICH regions.
Lynda Paleshnuik | 4-5 April 20117 |
New guideline development processNew guideline development process
A guideline updated according to current requirements, and
adopting CTD format, was needed.
� CTD formatting: (crafting of preparation document, plus
formatting of quality document) → initial draft
� guideline populated with quality technical guidance
- updated according to current practice
- including additional information on how to meet the
requirements
→ new draft
Lynda Paleshnuik | 4-5 April 20118 |
New guideline development processNew guideline development process
� Consultation process with PQP senior assessors (9) plus PQP
applicants (26) → new draft
� External consultation process (formal EC circulation)
→ final draft
� Presentation to EC on Specifications for Pharmaceutical
Preparations
Currently:
Preparation guideline adopted
Quality guideline provisionally accepted for pilot use in PQP
Lynda Paleshnuik | 4-5 April 20119 |
Introduction to the two documents
I: the preparation guideline
Introduction to the two documents
I: the preparation guideline
� assists applicants with the preparation of product dossiers
(PDs) for multisource products by providing general guidance
on the format of these dossiers;
� describes and adopts the modular format of the CTD as
developed by ICH;
� Provides guidance on the location of regional information
(Module 1) and other general data requirements.
� Primarily addresses the organization of the information, not
the studies required.
Lynda Paleshnuik | 4-5 April 201110 |
Introduction to the two documents
I: the preparation guideline
Introduction to the two documents
I: the preparation guideline
Lynda Paleshnuik | 4-5 April 201111 |
Adapting the CTD for new drugs
to CTD for generic drugs
Adapting the CTD for new drugs
to CTD for generic drugs
Regional
Admin
Information
Module 1
Nonclinical
Overview
Nonclinical
Summary
Clinical
Overview
Clinical
Summary
Quality
Overall
Summary
QualityNonclinical
Study Reports
Clinical
Study Reports
Module 3 Module 4 Module 5
Module 2
Not Part of
the CTD
The CTD
Lynda Paleshnuik | 4-5 April 201112 |
Introduction to the two documents
II: the quality guideline
Introduction to the two documents
II: the quality guideline
This guideline:
� assists applicants with the preparation of the Quality Module
of PDs for multisource products by providing general
guidance on the format;
� adopts the modular format of the CTD
� provides guidance on the technical and other general data
requirements (including preparation of the QOS-PD).
Lynda Paleshnuik | 4-5 April 201113 |
Key changes from the previous guidelineKey changes from the previous guideline
� CTD format adopted
� Updating of requirements
� Elaboration of how to meet quality requirements,
including full elaboration on the three ways to submit
API data:
- CEP
- APIMF
- full API data provided in the dossier
Lynda Paleshnuik | 4-5 April 201114 |
Key changes from the previous guidelineKey changes from the previous guideline
Reductions in requirements:
● fewer batches required to establish the FPP shelf-life
● process validation report for pilot batches no longer
required (replaced by uniformity demonstration for the
biolot)
● reduced process validation/pharmaceutical
development requirements for “established” generics
Lynda Paleshnuik | 4-5 April 201115 |
FPP batches to support the shelf-lifeFPP batches to support the shelf-life
Complicated FPPs:
● sterile products, metered dose inhaler products, dry powder
inhaler products and transdermal delivery systems.
● ritonavir/lopinavir FDC tablets and FDCs containing
rifampicin or an artemisinin.
Two pilot batches required
Uncomplicated FPPs e.g. immediate-release solid FPPs (with
noted exceptions), non-sterile solutions
One pilot batch and a second batch which may be smaller
(e.g. for solid oral dosage forms, 25 000 or 50 000 tablets
or capsules) are required
Lynda Paleshnuik | 4-5 April 201116 |
Biobatch uniformity demonstrationBiobatch uniformity demonstration
Process validation report for pilot batches no longer
required (replaced by uniformity demonstration for the
biolot);
Uniformity (biolot) can be demonstrated via blend
uniformity testing or extensive post-compression
uniformity testing or suitable sampling of packaged
product.
Lynda Paleshnuik | 4-5 April 201117 |
Established genericsEstablished generics
Products that have been marketed by the applicant or manufacturer
associated with the dossier for at least 5 years, and either 10
batches were produced in the past year, or 25 batches were
produced in the past 3 years.
Instead of process validation and certain pharmaceutical development
data, data provided as in Appendix 2, ie a product quality review
(PQR). The PQR replaces the developmental pharmaceutics data
in the sections on 1) formulation development (P.2.2.1 a)) and 2)
manufacturing process development (P.2.3 a)). In addition, it
replaces the section on process validation, P.3.5.
Lynda Paleshnuik | 4-5 April 201118 |
Navigating through the quality guideline
Section 1: introductory information
Navigating through the quality guideline
Section 1: introductory information
� Text includes bolded ICH M4Q text, and unbolded
additional WHO text
� ICH M4Q text revised to use WHO terminology:
► API/FPP, FDC, PD
► Generally refers to BE instead of clinical batches
� Presentation of the data is described for various
scenarios e.g. multiple APIs, multiple FPP strengths,
co-blistered FPPs, etc.
Lynda Paleshnuik | 4-5 April 201119 |
Quality document: quality summaries QIS/QOSQuality document: quality summaries QIS/QOS
Section 3: introduces the QIS/QOS
� The instructions for the QOS-PD run throughout the
quality guideline
� Instructions for the QIS are in Section 3.2 and preface
the QIS template
Lynda Paleshnuik | 4-5 April 201120 |
Quality document: Section 4 – module 3
Quality Data Sections
Quality document: Section 4 – module 3
Quality Data Sections
Section 4: QUALITY data in CTD format
Section 4 is divided (according to CTD structure) into:
3.2.S Drug substance (or API), and
3.2.P Drug product (or FPP)
Lynda Paleshnuik | 4-5 April 201121 |
Quality document: Section 4 – module 3Quality document: Section 4 – module 3
Three options for API information:
1. CEP – PhEur certificate of suitability
2. APIMF – API master file
3. Full details in the PD
Lynda Paleshnuik | 4-5 April 201122 |
Quality document: Section 4 – module 3Quality document: Section 4 – module 3
For CEP option (preferred option) – full description of the
sections and details for PD and QOS-PD given in the intro
For APIMF option, “the applicant/FPP manufacturer should
complete the following sections in the PD and QOS-PD in full
according to the guidance provided unless otherwise indicated
in the respective sections:”
S.1.1-S.1.3
S.2/S.2.1/S2.2/S.2.4
S.3.1/S.3.2
S.4.1-S.4.5; S5; S6; S7.1-S.7.3
Lynda Paleshnuik | 4-5 April 201123 |
Quality document: Section 4 – module 3Quality document: Section 4 – module 3
For full details in the PD option:
Information on the 3.2.S API sections should be submitted
in the PD as outlined in subsequent sections of this
guideline.
Lynda Paleshnuik | 4-5 April 201124 |
Quality Templates: QIS and QOS-PDQuality Templates: QIS and QOS-PD
QOS-PD = Quality Overall Summary – Product Dossier
The QOS is part of the ICH CTD structure of a
product dossier (PD). Replaces the PQIF (previous
quality template).
The QOS-PD is based on the CTD QOS,
modified/expanded to be of the most use to WHO.
Lynda Paleshnuik | 4-5 April 201125 |
QOS vs QISQOS vs QIS
QIS = Quality Information Summary = mini-QOS
� The QIS is a regional document. It is not part of the
CTD.
� The QIS is a document that helps with the efficiency of
the initial and subsequent assessment processes.
� Note that the QIS has an introductory page. The QOS-
PD does not, as the QOS instructions are found
throughout the quality guideline
Lynda Paleshnuik | 4-5 April 201126 |
QOS (all sections) vs QIS (bolded)QOS (all sections) vs QIS (bolded)
2.3.S DRUG SUBSTANCE (API)
2.3.S.1 General Information
2.3.S.2 Manufacture
2.3.S.3 Characterisation
2.3.S.4 Control of Drug Substance
2.3.S.5 Reference Standards or Materials
2.3.S.6 Container Closure System
2.3.S.7 Stability (container/storage conditions/retest only)
Lynda Paleshnuik | 4-5 April 201127 |
QOS (all sections) vs QIS (bolded)QOS (all sections) vs QIS (bolded)
2.3.P DRUG PRODUCT (FPP)
2.3.P.1 Description and Composition of the Drug Product
2.3.P.2 Pharmaceutical Development (batch summaries only)
2.3.P.3 Manufacture
2.3.P.4 Control of Excipients
2.3.P.5 Control of Drug Product
2.3.P.6 Reference Standards or Materials
2.3.P.7 Container Closure System
2.3.P.8 Stability (protocols, container/storage/retest)
Lynda Paleshnuik | 4-5 April 201128 |
Introduction to the QOS-PD templateIntroduction to the QOS-PD template
� Filled out by applicant as part of a PD
� Becomes the basis of the quality assessment report
► Data summarized in the QOS-PD is checked against
the official documents in the PD, e.g. specifications,
master production records, executed biobatch records
► Assessors’ remarks/questions/conclusions are
added, creating the assessment report.
Lynda Paleshnuik | 4-5 April 201129 |
Introduction to the QOS-PD templateIntroduction to the QOS-PD template
The QOS begins with a reference to the Q guide (1.5, 3 and
4) for general/detailed instructions.
Introductory information
Cross-references
Compendial references
Lynda Paleshnuik | 4-5 April 201130 |
Introductory Info
Cross-referencing
Introductory Info
Cross-referencing
Cross-referencing: to minimize the duplication of effort
(both assessors and applicants).
Example: Same API from same API manufacturer(s): depending on
the dossier, this may substitute for most of the API information
(current API specs required).
Lynda Paleshnuik | 4-5 April 201131 |
Introductory Info
Cross-referencing
Introductory Info
Cross-referencing
� Same API-excipient combination or API-API/excipient
combination in another PQ dossier– compatibility
data.
� Same excipients (same standards) in another PQ dossier
– excipient specifications.
� Same packaging system - including materials - as
another PQ dossier – packaging suitability tests (solid
orals), packaging specifications.
Lynda Paleshnuik | 4-5 April 201132 |
Introductory Information
Compendial References
Introductory Information
Compendial References
Listing of all available monographs for the officially
recognized compendial references of PQP
Specifications for the API and FPP should be developed
with the available monographs in mind
e.g. impurities identified in available API monographs
should be investigated (unless justified); demonstrate:
the absence of the impurities, or the ability of the in-house
method to control them, or exclusion from routine
analysis
Lynda Paleshnuik | 4-5 April 201133 |
Introduction to the QOS-PD templateIntroduction to the QOS-PD template
QOS-PD is divided (according to CTD structure) into:
2.3.S Drug substance (or API), and
2.3.P Drug product (or FPP)
Note that corresponding sections in the quality guideline
are numbered 3.2.S and 3.2.P, etc.
This reflects the location in the CTD modules:
● QOS-PD is in module 2 section 3
● Quality data is in module 3 section 2
Lynda Paleshnuik | 4-5 April 201134 |
Introduction to the QOS-PD templateIntroduction to the QOS-PD template
Some expansions compared to CTD QOS:
● Addition of tables (solubility, specifications, etc)
● Stability protocol sections expanded to include the
various stability categories: commitments for primary
batches, production batches, ongoing (annual) batches.
● Batch summaries in Section P.2.2.1 Formulation
Development (p. 14-15 of 26).
● Additional standard templates for summarizing
chromatographic methods and their validation.
Lynda Paleshnuik | 4-5 April 201135 |
Introduction to the QIS templateIntroduction to the QIS template
� Filled out by applicant as part of a PD
� The QIS is mainly cut-and-pasted information from the
QOS-PD, therefore much of it does not need to be
separately assembled.
� Includes agreed commitments made by the applicant.
The final QIS represents the PQ’d quality data.
Lynda Paleshnuik | 4-5 April 201136 |
Introduction to the QIS templateIntroduction to the QIS template
For each Question & Answer round to the applicant, there will
usually be a compiled question regarding the QIS as follows:
You are requested to submit a revised QIS in electronic format,
incorporating all of the changes requested in the preceding
comments. In addition,
<e.g. correct the specifications table impurity limits according
to the signed specifications>
<e.g. add the unit/block numbers to the addresses>
<e.g. correct formulation tables to be in agreement with
master production records>
Lynda Paleshnuik | 4-5 April 201137 |
Uses of the QIS templateUses of the QIS template
� Provides summary of the key quality data
� For variations, the approved/PQ’d data is easily found
for comparison
� Simplifies requalification assessment (QOS or PQIF no
longer required)
� Tool for inspectors (sites, process validation protocol
codes, commitments)
Lynda Paleshnuik | 4-5 April 201138 |
Tips - QISTips - QIS
� The initial QIS should be created by cutting and pasting
those sections which are common with the QOS.
� As the QIS will usually need to be revised and
submitted with each round of questions, the applicant
should list all changes to the QIS or confirm that no
unsolicited changes were made.
Lynda Paleshnuik | 4-5 April 201139 |
Implementation datesImplementation dates
PDs in CTD format can be submitted now but are
optional.
For all PDs submitted after 1 March 2011, the QOS-
PD and QIS are mandatory.
CTD format dossiers are encouraged at this time.
They are mandatory in PQP after 1 September
2011.
Lynda Paleshnuik | 4-5 April 201140 |
Thank youThank you
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