Meeting with Medicine Manufacturers Geneva – 4-5 April … · Meeting with Medicine Manufacturers Geneva – 4-5 April 2011 The New Quality ... Format; “Quality” ... Consultation

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


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


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


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


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


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.


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


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


Introduction to the two documents




� 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.







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






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).


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


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


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


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.


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.


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.


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


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)


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



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



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.


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.


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


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)


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)


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.



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


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).


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.


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



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



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.


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.


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>


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)


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.


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.


Thank youThank you

Documents

Meeting with Medicine Manufacturers Geneva – 4-5 April … · Meeting with Medicine Manufacturers Geneva – 4-5 April 2011 The New Quality ... Format; “Quality” ... Consultation