Role of QC/Production/QA in relation to batch release

Beijing University 20-22 September 2006

Lionel Viornery Inspector, head of the starting materials for pharmaceutical use inspection unit

Role of QC/Production/QA in relation to batch release

Introduction

From the finished product point of view From the API point of view

General GMP requirements Role of QA/QC/Prod in batch release Conclusion

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Introduction

The release is a concept included in EU

legislation applicable to finished products Article 51 of directive 2001/83/EC and article 11 of directive 2003/94/EC

EU GMP Part I (Principle) : The holder of a

Marketing Authorisation (MA) holder must manufacture medicinal products so as to ensure:

They are fit for their intended use They comply with the requirements of the MA They do not place the patients at risk due to inadequate safety, quality or efficacy

Introduction

The release is a concept included in EU

is released for sale or supply :

legislation applicable to finished products

EU GMP Part I (section 1.4) : No batch of product

Until the quality has been judged to be satisfactory Prior to certification by a Qualified Person (QP) that it is in accordance with the requirements of the MA Prior to certification by a QP that each production batch satisfies the provisions of Article 51 of EU Directive 2001/83/EC

Introduction

EU GMP Annex 16 Certification by a QP and

batch release

Section 2 : Purpose of controlling batch release is :

to ensure that the batch has been manufactured and checked in accordance with the requirements of the MA, the principles and guidelines of EU GMP and any other legal requirement before it is placed on the market In the event that a defect needs to be investigated or a batch recalled, to ensure that the QP who certified the batch and the relevant records are readily identifiable

Introduction

EU GMP Annex 16 (continued)

ensure that :

Section 8 : Before releasing a batch, the QP should

The batch and its manufacture comply with MA Manufacture carried out in accordance with EU GMP Principal manufacturing and testing processes validated Any deviations or planned changes in production or QC authorized internally and notified/authorized by the relevant authority All necessary production and quality control documentation completed and endorsed All audits carried out as required by the QA system Any other factors relevant to the quality of the batch taken into consideration

Introduction

From the API point of view

27 occurrence of releas in EU GMP Part II for
APIs (release, releasing, released)

Glossary of EU GMP Part II for APIs

Manufacture : All operations of receipt of materials, production, (re)packaging, (re)labelling, quality control, release, storage and distribution of APIs and related controls Release : ?

Introduction

Release

1- Solvent 2- API SMaterial 1 3- API SMaterial 2

Reaction

Crude API

Crystallisation

Pure API (dried)

Release ?
Pure API (wet) Drying Isolation

Pure API in solution

Packaging/ labelling

Pure API in containers Distribution

Drug Manufacturers

Release
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Introduction

Tentative definition for release

Decision making process allowing the authorised
persons to permit the use of the material or its distribution

In doing so, the authorised persons ensure that :

Materials meet established specifications (case of raw materials and Intermediates) APIs meet the requirements for quality and purity that they purport or are represented to possess APIs meet the commitments made in registered files (MA, CEP, ASMF)

Role of QC/Production/QA in relation to batch release

Introduction General GMP requirements Role of QA/QC/Prod in batch release Conclusion

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GMP requirements in relation to batch release activity

Release in relation to

Raw materials (sections 7.20 and 7.21) Packaging and labelling materials Intermediates (section 2.22-1) API (section 2.22-1)

(section 9.10)

Release for internal use

10.20)

Raw materials and intermediates

(sections 2.17 and

Release for distribution

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Intermediates and final API

(sections 2.17 and 10.20)

GMP requirements in relation to batch release activity

Principles : What
Section 2.17 : No materials should be released
or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in section 10.20 or the use of raw materials or intermediates pending completion of evaluation)

QA unit is responsible for the release of all materials Use or distribution of raw materials and intermediates under quarantine is possible under conditions
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GMP requirements in relation to batch release activity

Principles : What
Section 10.20 : APIs and intermediates should
only be released for distribution to third parties after they have been released by the Quality Unit(s). APIs and intermediates can be transferred under quarantine to another unit under the companys control when authorised by the Quality Unit(s) and if appropriate controls and documentation are in place

QA unit is fully responsible for the release of APIs and Intermediates to third parties Distribution or use under quarantine is possible in the case of a unit of the same company for example
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GMP requirements in relation to batch release activity

Principles : How
Section 6.70 : Written procedures should be
established and followed for the review and approval of batch production and laboratory controls records, including packaging and labelling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed

The release process should be described in a procedure detailing the different steps to be followed, documentation to be reviewed (including deviations), who will release
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GMP requirements in relation to batch release activity

Principles : Who
Section 2.14 : The persons authorised to release
intermediates and APIs should be specified

Section 3.11 : The responsibilities of all personnel

engaged in the manufacture of intermediates and APIs should be specified in writing

The responsibility for releasing APIs, materials, intermediates specified in writing for all the persons in charge (including deputies); Responsibility usually included in individual job descriptions
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Situation observed in the field

Release Raw materials Non isolated intermediates for internal use Isolated intermediates for internal use Intermediates for distribution APIs for distribution

Production No Yes Yes No No

QC Yes No Yes No No

QA No No No Yes Yes

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Role of QC/Production/QA in relation to batch release

Introduction General GMP requirements Role of QA/QC/Prod in batch release Conclusion

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Role of QA, QC and production in batch release

Role and responsibilities of QA unit in the batch

release process

Section 2.22 : Responsibilities of the independent

quality unit(s) should include :

Releasing or rejecting all APIs and Intermediates for use outside the control of the manufacturing company; Establishing a system to release or reject raw materials, intermediates, packaging and labelling materials

QA unit is fully responsible for API and intermediates release QA unit can delegate the release of all the other materials to other departments (QC and/or production) except intermediates for third parties
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Role of QA, QC and production in batch release

Role and responsibilities of QA unit in the

release process Sections 2.22-3 et 6.71 : QA unit(s) should review and approve batch production and laboratory control records of critical process steps

Section 6.71 : QA unit(s) should implement and

approve procedures in case of delegation to other unit(s) of the review of the production and laboratory control records of non-critical process steps

Critical meaning something that must be controlled within predetermined criteria to ensure that the API meets its specification
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Role of QA, QC and production in batch release

Role and responsibilities of QA unit in the

release process Section 6.72 : All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released

Section 11.43 : Authorised personnel of the

Quality Unit(s) should date and signe Certificates of analysis been reworked, appropriate evaluation demonstrating the equivalence in quality of the reworked batch should be performed

Section 14.3 : In the case of batches that have

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Role of QA, QC and production in batch release

Before releasing the batch and signing the CoA,

the authorised persons of the QA should check that :

The batch and its manufacture comply with the

registered file including the specifications

The process and analytical methods used for

testing have been validated (unless if included in the relevant Pharmacopoeia) properly monitored

Quality systems are in place, maintained and

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Role of QA, QC and production in batch release

Before releasing the batch and signing the CoA,

the authorised persons of the QA should ensure that : (continued) All production and QC documentation has been completed, reviewed and signed

Any deviation (including reworking) have been

investigated and the impact on the quality of the API assessed can impact the quality of the API have been notified and authorised by the dosage form manufacturer

Any planned changes in production or QC that

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Role of QA, QC and production in batch release

Role and responsibilities of Production unit in

the release process Section 2.3-3 : Production should review all production batch records and verify these are completed and signed

Section 2.3-4 : Production should ensure that all

production deviations are reported and critical ones are investigated and conclusions recorded should review records of non-critical process steps if delegation by the quality unit(s) exists according to procedures approved by QA

Section 6.71 : Qualified production personnel

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Role of QA, QC and production in batch release

Role and responsibilities of QC unit in the

release process

QC should ensure through appropriate testing

that raw materials, intermediates, packaging and labelling materials, and APIs are compliant with established specifications and standards records including data derived from all tests carried out and conclusions recorded

Section 6.60 : QC should maintain complete

QC should ensure that all OOS are investigated

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Role of QA, QC and production in batch release

CONCLUSION

Batch release is the one minute decision result

of several weeks of work

This decision should result from the review of

factual evidence (BPR, results from testing) and should be backed by a living Quality System an increase in the requirements for the release of RM versus APIs unit to the user, the drug manufacturer

A certain flexibility exists in EU GMP Part II with

Batch release is a strong commitment of the QA

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