How and Where to Control and What to Put in the File Setting - - PowerPoint PPT Presentation

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How and Where to Control and What to Put in the File Setting - - PowerPoint PPT Presentation

Sep 30, 2022 339 likes •519 views

How and Where to Control and What to Put in the File Setting specification: Session 4 Kowid HO London, 9 September 2011 1 Control of raw and starting materials Product Control of Control of process intermediates parameters QUALITY

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How and Where to Control and What to Put in the File

Setting specification: Session 4

Kowid HO London, 9 September 2011

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1

Product Process

Control of raw and starting materials Control of intermediates Control of process parameters Control of drug substance and drug product Process validation & evaluation Good manufacturing Practice

QUALITY QUALITY

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2

How to control

  • Control Strategy (ICH Q10) :

– A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. – The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

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How to control

  • Quality Attributes

– Directly controlled at relevant step(s) – Indirectly controlled at relevant step(s) – e.g. surogate QA… – Parametric control(s) at relevant step(s) – e.g. causality and/or correlation between PP(s) and QA(s), design space… – Process robustness – e.g. demonstration of high clearance capability…

  • Process parameters

– Directly controlled – Indirectly controlled – e.g. correlated to other parameter(s)… – Procedural – e.g. sequence of operation…

  • “Limits”:

– Acceptance criteria – Internal action limits

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How to control

  • Frequency of monitoring and control.

– Routine

  • Performed for each run

– Periodic

  • Performed at defined frequency and/or

conditions (e.g.: skip testing, revalidation, continuous process verification…)

– Occasional

  • Performed in specific situations (e.g.

evaluation/validation, characterisation, comparability, investigation…)

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How to control

  • Alternative to routine end-product testing

– Full testing according to the specifications may be required during a running in period – Real Time Release

  • Ability to evaluate and ensure the quality of in-process

and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls

  • RTR testing applicable to Drug Product, Drug Substance,

and Intermediates

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Where to control

  • Routine testing approach and/or a validation approach:

– Routine testing approach: monitoring of the quality attribute at appropriate step(s) of the process, in order to ensure acceptable levels in the final product. – Validation approach: based on evidence of successful validation of the manufacturing process (e.g. establishing consistent and satisfactory impurity clearance); in such situation, process monitoring may be carried out without direct measurements of the quality attribute. – Combination of routine testing and validation approaches (e.g. routine testing at an earlier step of the purification process and demonstrated reduction by validation in order to ensure a limit at the final product level, if tested).

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Starting material DS intermediates Drug Substance DP intermediates Drug Product Raw materials / Excipients

Specification (release/shelf-life)

Where to control

Specification (release/shelf-life) Specification (release/shelf-life) In-process test (Acceptance criteria Action limits) In-process test (Acceptance criteria Action limits) Specification (release/shelf-life)

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Where to control

Case study 1: “Routine testing approach” …

…

Eluate Y Column X

PP (b) PP (c)

Bioreactor

PP (a)

Eluate X Harvest

Sufficient clearance capability NOT demonstrated Impurity formation ROUTINE TESTING

DS Column Y

QA (b) QA (c) QA (a) QA (d) PP (d)

Not routinely tested Not routinely tested Not routinely tested

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…

…

Eluate Y Column X

PP (b) PP (c)

Bioreactor

PP (a)

Eluate X Harvest

Sufficient clearance capability DEMONSTRATED Impurity formation

DS Column Y

QA (b) QA (c) QA (a) QA (d) PP (d)

Where to control

Case study 2: “Validation approach”

Not routinely tested Not routinely tested Not routinely tested Not routinely tested

  • r

Periodic testing

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Where to control

Case study 3: “Routine testing & Validation approach” …

…

Eluate Y Column X

PP (b) PP (c)

Bioreactor

PP (a)

Eluate X Harvest

Moderate clearance capability (e.g. 3 log reduction) Impurity formation

DS Column Y

QA (b) QA (c) QA (a) QA (d) PP (d)

Low to Moderate clearance capability but low level (e.g. <1000ppm) ROUTINE TESTING Not routinely tested Not routinely tested

  • r

Periodic testing Not routinely tested

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Where to control

Case study 4: “Enhanced approach” …

…

Eluate Y Column X

PP (b) PP (c)

Bioreactor

PP (a)

Eluate X Harvest

Impurity formation

DS Column Y

QA (b) QA (c) QA (a) QA (d) PP (d)

PAT Sufficient clearance capability DEMONSTRATED when operating within DESIGN SPACE Not routinely tested

  • r

Periodic testing Not routinely tested Not routinely tested

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What to Put in the File

  • Marketing Authorisation Application

– Justification of control strategy:

  • Justification of drug specification (S.4.5 and P.5.6)
  • Specifications release and shelf life (S.4.1 and P.5.1); should comply with them if

tested

– Process description (scale, column characteristics…) and control (CPP, non-CPP, acceptance criteria, action limits…):

  • Description of manufacturing process and process controls (S.2.2 and P.3.3),
  • controls of critical steps and intermediates (S.2.4 and P.3.4),

– Description of control of materials

  • Control of materials (3.2.S.2.3),
  • Control of excipients (P.4),

– Process evaluation/validation

  • Results of in-process tests (S.2.5 and P.3.5) and batch analyses (S.4.4 and P.5.4)
  • n an appropriate number of consecutive batches produced with commercial

process and scale

  • Evaluation of relevant process steps and/or intermediates (hold time, clearance…)

– Evolution of the control strategy

  • Description in manufacturing process development (S.2.6).
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What to Put in the File

  • Marketing Authorisation Application with enhanced

product/process evaluation

– Justification of control strategy

  • Comprehensive mapping of tests and acceptance criteria/action limits
  • Justification of how and where tests are performed

– Process evaluation/validation

  • Detailed information on studies (DOE, analysis, outcome…)

– Depending on study design, objective and outcome, could justify:

  • Alternative to end product testing (RTR testing…)
  • Leverage data requirement for process validation (protocol for

continuous process verification…)

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What to Put in the File

  • Marketing Authorisation Application with enhanced

product/process evaluation and design space

– Justification of control strategy

  • Comprehensive mapping of tests and acceptance criteria/action limits
  • Justification of what, how and where tests are performed
  • Comprehensive information of risk ranking/filtering tool used

– Process description and control

  • Clear description of step covered by design space(s)
  • Summary of design space(s)

– Process evaluation/validation

  • Detailed information on studies (DOE, analysis, outcome…)
  • Interaction between CQA(s) and CPP(s)

– Depending on study design, objective and outcome, could justify:

  • Alternative to end product testing (RTR testing…)
  • Leverage data requirement for process validation (protocol for continuous process

verification…)

  • Reduced details for process description and control (scale, acceptance

criteria…)

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MAA

+ Enhanced evaluation (e.g. DOE) + Design space Specification Justification +++ Justification +++ Justification +++ CQA Risk ranking filtering tool +/- + +++ CPP interaction with CQA +/- ++ +++ Process description and control +++ +++ + (depends on aspects covered by design space) Alternative to end product testing

  • +

(depends on study design and outcome) + (depends on study design and outcome) Process evaluation +/- ++ +++ Process validation +++ Detailed results of IPT and batch analyses on consecutive batches (final scale and process) ++ Detailed results of IPT and batch analyses on consecutive batches (final scale and process) Could be leveraged from process understanding + Mainly based on process evaluation + continuous process verification