Feedback EMEA / Industry Discussion Eli Lilly & Co Ltd Case - - PowerPoint PPT Presentation

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Feedback EMEA / Industry Discussion Eli Lilly & Co Ltd Case Study: Use of In-Line Near-Infrared Spectroscopy to Monitor Segregation of a Pharmaceutical Powder Blend in a Tablet Press Martin Diller PhD, Federal Institute for Drugs &

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29/09/2009 EMEA/Efpia QbD Application Workshop - London

Feedback EMEA / Industry Discussion Eli Lilly & Co Ltd Case Study: Use of In-Line Near-Infrared Spectroscopy to Monitor Segregation of a Pharmaceutical Powder Blend in a Tablet Press

Martin Diller PhD, Federal Institute for Drugs & Medical Devices (BfArM), Germany John Kerridge PhD, Eli Lilly & Co Ltd, United Kingdom

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  • Real time powder uniformity monitoring

during compression

  • Non-contact NIR probe
  • Technique allows for :-

– rapid & non-destructive content uniformity assessment – segregation determination of the blended materials, both API and excipients, going directly into the final pharmaceutical solid dosage form, i.e. tablet.

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Case Study Summary

NIR probe positioned in Fill-o-matic Feeder Frame, prior to tablet

  • compression. ~ 10

– 15 mm from tablet die.

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Case Study Summary

– NIR System - Rapid data acquisition times (<35 milliseconds per spectrum) – Shown to provide an alternate strategy for demonstrating adequacy of mixing of powder blends – Excellent potential to monitor a larger fraction of the entire blended sample preparation

– Improved statistical description of variation within an entire production batch.

– Improvement on PQRI Draft Guidance recommendation

– of using stratified sampling of both the blend and dosage units at specifically targeted locations

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Case Study Summary

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50 100 150 200 1 2 3 4 5 6 7 Elasped Tim e, m inutes Concentration, % N I R E stim ate H PL C M easur em ent

Layered powder fractions of differing concentration in tablet hopper

NIR Data

% Drug Content Layered in chute

Accurate product monitoring in real-time throughout the batch

5.5% 4.5% 4.0%

4.5%

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Case Study Summary

  • Conclusion

– In-line NIR method provides for an additional tool in the QbD/PAT tool box – Can be used to assess and identify critical sources of process and product variability

  • Eg correlating properties such as particle size, shape,

density, surface texture, cohesiveness, etc. to powder flow and uniformity – Enables production of a more consistent product that meets predefined critical quality attributes. – With development may provide an opportunity for alternative product testing strategies

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Main Topics Discussed

  • Technical questions
  • Introduction of novel technologies

– Data required in submissions – When does “novel” become “platform”

  • Development – improving Process /

Product Knowledge

– Traditional versus “monitoring” sampling techniques – Data presentation for assessment (quantity/section) – Bridging studies between traditional and novel techniques – Pure process knowledge information – does it need to be presented for review

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Main Topics Discussed

  • Design space / Control strategy

– Data for process understanding / development purposes – Potential use as “real time release test”

  • Regulatory Framework

– Current regulatory framework changes needed to enable implementation – Provision of timely advice on new CMC approaches

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Common Understanding

  • NIR spectroscopy is a potential and suitable tool for

controlling process and product quality

  • NIR could replace existing IPC
  • NIR could add to existing IPC to povide enhanced

information on manufacturing process

  • NIR measurement provides increased knowledge of

process variability

  • Increased sampling frequency (continuous verification)
  • Does this provide a basis for changing conventional

thinking and decision making ?

  • EMEA NIR guidance is currently under review

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Common Understanding

  • Concept development

– Potential for technique to replace end-product-testing (real time release testing) – Thorough risk assessment and evaluation needed – Understand key parameters

  • Eg impact of machine type, influence of excipients
  • Dossier submissions for new technologies

– Explain concepts, science and summarise key data – Supporting information eg spectra would be reviewed at inspection

  • A PAT defined control strategy would need to be fully

integrated into a Quality Management System

– Eg . Atypical results, Out of specification process – Strategy may be specific to technology / technique

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Areas for further work

  • Defined structures for training and advice are necessary

(industry and regulators)

  • e.g. workshops, presentation s on new PAT

approaches

  • Take opportunities for using EMEA PAT team and

Scientific Advice procedures

  • accurate definitions, interactive dialogue, accepted

agreements

  • Regulatory guidance should be adjusted appropriately
  • e.g. Variations, NIR, RTR testing, process validation

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Areas for further work

  • Changing the perspective – different approaches may

match or improve on traditional methods through analysis

  • f different information

– Eg Uniformity of dose could be replaced by continuous evaluation

  • f powder blend uniformity and tablet weight
  • “New” technology principles need to be explained

– Statistical approaches

  • Ensure approaches (data filtering) are scientifically valid

– Eg use of standard diagnostic techniques

  • How to demonstrate that the data analysis has looked at the

positive and negative influences on the data set ?

  • Where best to describe data analysis models ?

– Consider industry / regulator training programmes on specific techniques - Eg Multivariate data analysis

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Conclusion

  • In-line estimation of API concentration of a flowing

powder in a tablet press has been demonstrated using a NIR probe and a good chemometric model.

  • Further development may allow traditional control and

testing strategies to be changed – continuous verification

  • Successful development and implementation of such

techniques will require discussion and adaptation of regulatory frameworks & submission content

  • Regulators and industry share common views on what

can be achieved – further discussion to allow successful implementation will continue

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