International Pharmaceutical Excipients Council of the Americas
Excipient Composition Committee Meeting
Buchanan Ingersoll Law Offices
1700 K St NW (3rd Floor) Washington DC, SUITE 300
May 24, 2011 (Wednesday, 1.00 pm – 4.30 pm)
Visible Particles Working Group – Summary of Discussions
The following points were raised during the wide ranging discussion of the Visible Particles
document. The points have been recorded in the approximate order they were made, some
points were raised more than once, and are thus recorded more than once:
1. Definitions of visible particles required – objectionable and non-objectionable.
2. Some particles are inherent to a particular material and/or processing. Ideally they
should not be there, but are an unavoidable consequence of using a particular raw
material or reagent.
3. Non-objectionable particles would particles having no impact on patient safety,
i.e. can the product meet its performance specification (QTPP/CQA in QbD
terms).
4. Some level of visible particles will be found (zero is not an option). The question
is how they impact the final product; can they be processed out; or can they be
masked, and how?
5. Acceptability relates to size and quantity.
6. Foreign particles should not be there. They are not inherent to the raw materials or
reagents.
7. ICH Q3A section on extraneous contaminants was mentioned.
8. Precautions excipient user might take.
9. Precautions excipient manufacturer might take.
10. Need to establish a baseline; particulate counts recorded over time.
11. Example: one particle found in one drum by the user; actions to be taken:
• Go back to manufacturer
• Joint assessment
- Communication
- Partnership
12. Particle etiology – where did it come from?
13. Food industry standards – levels of extraneous contaminants.
14. What is reasonable?
• Not an excuse for poor GMP.
15. Environmental standard – technology to achieve an acceptable minimum
• Control technologies
• Best that industry can do
16. Scale of excipient manufacture.
17. Risk management concepts to be brought in.
• What is a reasonable risk mitigation approach?
• Maker/user agreement on a case by case basis
- Both need to use the same methodology and terminology.
18. Looking to develop a process by which we can establish what the specification for
visible particles should be.
19. We will not be able to establish limits per se since they will change with the
excipient, the application, the user and the manufacturer.
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International Pharmaceutical Excipients Council of the Americas
Excipient Composition Committee Meeting
Buchanan Ingersoll Law Offices
1700 K St NW (3rd Floor) Washington DC, SUITE 300
May 24, 2011 (Wednesday, 1.00 pm – 4.30 pm)
20. Black bits is a resource intensive issue for both the user and the manufacturer.
21. Purpose has been defined. There was much discussion around inherent. There appears
to be some confusion and clarification may be needed.
22. The scope needs to be redefined; not an excuse for implementation of poor GMP.
23. Document needs sections on:
• ‘Background’ section to be written (Ann Van Meter)
• Origins of visible particles
• Ishikawa diagram
- Need to define all terms listed in the Ishikawa diagram which are not
included in the consolidated IPEC Glossary.
• Define ‘unrelated material’ (Ann Van Meter and Priscilla Zawislak).
24. Need to develop a process flow for the resolution of visible particle issues.
• Identify particle
- Assess likelihood or origin
• What are the options?
- Is it toxic, (objectionable), acceptable or unacceptable?
• Risk assessment/mitigation
- Control points\
 Screens
 Magnets
 Filters
- Proactively look at process using e.g. FMEA
- Need to assess before upgrade excipient manufacturing plant or design
new plant
• Need to include communication between maker and user as to what is a
‘normal’ level of visible particles expected to be present in an excipient.
25. Summary points for makers:
• FMEA assessment
• Develop a sampling plan
• What are you doing, why are you doing it, and does it make sense?
• Investigation process/procedure for when unexpected particles are found.
• Mitigation strategy
- Regular inspections
- Rare earth magnets
- Screens
- Filters
- Etc.
26. Summary points for users:
• Communicate with the maker
- Starts when begin to qualify excipient
 Include discussion on visible particles
- QbD due diligence
 Part of design process
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International Pharmaceutical Excipients Council of the Americas
Excipient Composition Committee Meeting
Buchanan Ingersoll Law Offices
1700 K St NW (3rd Floor) Washington DC, SUITE 300
May 24, 2011 (Wednesday, 1.00 pm – 4.30 pm)
•
•
•
Define reasonable expectations for visible particles based on supplier
capability and intended use of the excipient.
Supplier audits (not just GMP audits)
- Visible particles should be a discussion during supplier audits
 What is likely
 Source
- Audits in future may be split; GMP vs. technical review/discussion
 Patient safety issues
 Excipient performance/product performance issues
Before send particles to contract laboratory for investigation, discuss with
maker.
- Send to maker if agreed.
RCM/rcm 20110623
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