Particulate Contamination

J.M. Morris, HPRA

PDA Hilton Hotel, Charlemont Place, Dublin 10th November 2015

European Regulatory Considerations

Overview

• Definitions

• Guidance notes

• Pharmacopoeial considerations

• Particulate contamination in eye preparations

• The future

2 24-Nov-15

Ph. Eur: Parenteral preparations (0520) • Definition section of the monograph • Solutions for injection or infusion are clear and

practically free from particles when examined under suitable conditions of visibility

• Comply with test for sub-visible particles • Other compendia use similar description -

“essentially” free from particles (USP) etc. • This in effect recognises that the complete

absence of particles is difficult to attain and even more difficult to prove

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Visible particulate contamination

• Injections/infusion should be free of particles

• Routine visual inspection

• Conducted after filling vials/ampoules

• Containers are designed to permit visual inspection of injections before use

• Pharmacists and other HCP’s trained to inspect ampoules and vials and reject those with a single-visible particle (≈40µm)

24-Nov-15 4

Regulatory Considerations • No specific regulatory guidance in EU – case

by case approach • Regulators rely on pharmacopoeial standards

and have seen no need to develop additional guidance so far

• Possibility of particulate matter being a problem should perhaps be addressed at the development phase of a product

• This might cover nature of the product/formulation/manufacturing process/proposed storage etc

24-Nov-15 5

Regulatory Considerations 2 • Simple solutions should not be a problem –

unless solubility might change over time • More complex products - colloids, emulsions, micellar formulations - biological macromolecules may need special attention • Manufacturing process effects – e.g. sterilisation, mixing/agitation, temperature

changes might result in precipitation

24-Nov-15 6

Regulatory Considerations 3- pharmaceutical development • Active substance-solubility, polymorphism,

moisture content: may determine solution issues and changes on storage

• Excipients in the formulation may interact over time and modify solution properties

• Excipients used as stabilisers e.g. albumin may precipitate /aggregate over time leading to appearance of particles

24-Nov-15 7

Regulatory issues 4-development cont.

• Container closure interactions may result in leaching of additives which might effect solubility of key components e.g. plastics

• Container itself may shed surface particles e.g. delamination of glass

• Revision of Ph. Eur. Monograph on glass containers (04/2015: 30201)is addressing this issue.

24-Nov-15 8

Glass containers for pharmaceutical use 3.2.1

• New production section deals with delamination • Aggressive conditions can result in separation of

inner glass surface into lamellae ( flakes) over time • Risk factors include temperature, pH, buffers such

as citrate or phosphate, ionic strength etc. • Assess propensity for delamination during

development by use of accelerated degradation testing

• Webinar on this topic at EDQM on 10/12/2015 – drpd.edqm.eu

24-Nov-15 9

webinar on this to.10/12/2015 –drpd.edqm.eu

Determination of visible particles in parenteral preparations • Simple visual examination in front of

illuminated white and black backgrounds (Ph. Eur. 2.9.20)

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Determination of sub-visible particles (Ph. Eur. 2.9. 19) • Method 1 Light obscuration test is the preferred method • Acceptance criteria - > 100ml volume NMT 25 particles/ml 10µm or more NMT 3 particles/ml ≥25µm - 100ml or less 6000 per container >10µm 600 per container >25µm • Where method I cannot be used (reduced clarity or

increased viscosity) – method 2 can be used Examples – colloids, emulsions, liposomal preparations

24-Nov-15 11

Sub-visible particles continued Method 2: Microscopic particle count Membrane filtration followed by direct observation of the filter surface with a microscope fitted with ocular micrometer Acceptance criteria > 100ml nominal volume NMT 12 particles/ml> 10µm NMT 2 per ml > 25µm 100ml or less NMT 3000 particles >10µm 300 “ >25µm

24-Nov-15 12

ICH and Harmonisation • ICH, Q6A, Q6B and Q8 pharmaceutical development are

relevant to this topic • Sub-visible particles – test has been harmonised by the

Pharmacopoeia Discussion Group (PDG) • One of a number of general methods recommended to PDG

from the ICH Q6A discussion (PDG topic Q09) • Same text and acceptance criteria now harmonised in JP, Ph.

Eur, USP • The only difference is the 100ml nominal volume – in Japan treated as LVP – i.e. stricter limits – in EU + US treated as svp • This might be a problem in practice since 100ml minibags

are very common

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Role of ICH Q4B group activities

• Evaluation and recommendation of pharmacopoeial texts for use in ICH region

• Q4B guideline sets out the process and provides a set of topic specific annexes

• Annex 3 deals with the test for particulate contamination (EMEA/CHMP/ICH/561176/2007)

24-Nov-15 14

Role of ICH Q4B group activities continued • Interchangeability declared with one condition • 2.2 “At the 100ml nominal volume the criteria in JP are more

strict than those in Ph. Eur. and USP.” • If JP followed then the product will meet Ph. Eur. And USP

requirements • Effective date December 2008 • Provides a once-off declaration of interchangeability and

avoids individuals having to make their own comparisons • Published on ICH website with the other 16 Q4B annexes • General Chapter 5.8 on pharmacopoeal harmonisation

provides an overview of this work

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Parenteral Preparations • The requirement for compliance with the test for

particulates comes from the Ph. Eur. general monographs on parenterals (0520)

• This forms one of the group of dose form monographs which have mandatory applicability to all products

• Consequently all parenteral products must comply with the requirements of (0520) although there are exceptions for certain blood products, radiopharmaceuticals, immunologicals and certain products for veterinary use

• However all injections and infusions for human use comply with the harmonised test for particulate matter

24-Nov-15 16

Ph. Eur Group of Experts 12 • The dose form monographs have been developed and

amended by Group 12 on a regular basis • Additions or amendments to these texts are added to the

work programme of the group with the agreement of the Ph. Eur. Commission

• Membership of Group 12 includes academics, industrial experts and regulators

• New/revised texts are published in Pharmeuropa for a comment period, after which they are submitted to Ph. Eur. Commission for adoption

• It generally takes about 1 year between adoption and implementation

• The group also provides expertise to advise Commission on relevant general tests like Particulate contamination and other tests in the PDG process

24-Nov-15 17

Sub-visible particle quantitation in protein therapeutics • Stimulus article in Pharmacopoeial Forum (US) and Pharmeuropa

(EU • Increasing numbers of parenteral preparations containing proteins • These often have different characteristics than conventional

parenteral products - small volumes - increased possibility of coming out of solution - use of protein stabilisers for example albumin - protein aggregation issues • Recognised that existing particle measurement methodology may

not always be the most useful for such products • USP published new chapter <787> - subvisible particulate matter in

therapeutic protein injection

24-Nov-15 18

Sub-visible particles in protein therapeutics 2

− Opening statement “This chapter can be used as an alternative to USP

chapter Particulate matter in Injections <788> − Concern expressed that such a statement might

represent a threat to the harmonised chapter in PDG Q09 particulate matter in injections

− USP concurred with this view and proposed to delete the statement from <787>

− This has led to proposals for revision of PDG Chapter Q09 – Particulate matter in injections

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Proposed revision of Q – 09 (2015) 1. Revision to describe three types of particle

that can be detected by the method 2. Flexibility in sample aliquot size – large

samples in the current procedure problematic for products manufactured in small volumes and delivered in small volumes (availability; cost)

3. Statement on particle size calibration standard from 5µm to 100µm to aid end users in the calibration

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Proposed revision of Q – 09 continued 4. Revision of particle limits in large volume parenteral

(LVP) product – introduce a ceiling particle load per container

5. Eliminate requirement for pooling SVP samples for the microscopy test – 25ml is necessary for method 1 (light obscuration) but, not for method 2 “Single units may be tested in an appropriate sampling plan”

6. Inclusion of new test – flow microscopy imaging based technology increasingly being used for formulation development application

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Proposed revision of Q – 09 continued • Revision of the text for Q09 should be addressed via

the normal PDG procedure • Important that we do not see individual

pharmacopoeias making changes unilaterally to harmonised texts

• When we have agreed harmonised texts it is clearly important to maintain the harmony and move forward prospectively to introduce improvements

• Group 12 is the main support group in Ph. Eur for this work and it is important that we identify the European experts to participate in this process

• Experts from Ireland welcomed

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Proposed revision of Q – 09 continued 1. Seems useful to expand the definition of types of

particles although it does not affect the methodology

2. Flexibility might be useful as long as it does not lead to subjective approaches and disharmony

3. Measurement of different particle sizes (below 10µM), larger aggregates – important for decreasing risk of immunological reactions

• Less aggressive sample handling conditions in the case of biological products is appropriate

24-Nov-15 23

Proposed revision of Q – 09 continued 4. Limit particle ceiling per container for LVP’s – seems to

have merit in reducing total particulate load administered to patients

5. Eliminate pooling of Method 2 - seems reasonable 6. New methods added – is it too early? - Group 12 is in favour of revision of chapter Q09 within the PDG process - Group 12 is not in favour of developing a chapter devoted to protein therapeutics since the issues raised are best addressed in the Q09 revision

24-Nov-15 24

Particulate levels in eye drops • Eye drops should not contain extraneous foreign

particles which abrade or damage the conjunctiva and cornea

• However risk is less than with parenteral preparations – some eye drops are presented as solid dispersions in a liquid phase

• Risks are difficult to quantify • Risk obviously significantly higher in an injured eye • Therefore there is merit in controlling particles in eye

preparations • Filtration through 0.2µm filter is usual during

manufacture • What standards to apply?

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Particulate levels in eye drops 2 • Products prepared commercially using blow fill seal

technology which can deliver low product particle counts • Smaller production scale may be manually filled in plastic or

glass eye drop bottles • Different levels of particulates may be achievable • JP standard – after filtration and microscopic examination

NMT 1 particle 300µm or greater allowed • USP <789> Particles in ophthalmic solutions

NMT 50 particles/ml≥ 10µm “ 5 particle/ml ≥ 25µm

• Tight standard – might include intravitreal, intracameral injections

24-Nov-15 26

Particulate levels in eye drops 3 • No Ph. Eur standard developed as yet • Discussion in Group 12 as to possible

development of a Ph. Eur standard, less stringent than USP

• Extensive work conducted in Netherlands via Laboratory of Dutch Pharmacists 1

• Work conducted on a large sample of different eye drops – examination of historical aggregated data measuring numbers of particles > 10µm and 25µm respectively

24-Nov-15 27 Ref. Dr C. Vermaat and colleagues 1

Particulate levels in eye drops 4 • Determined mean numbers of particles per ml

of a range of samples and applied Mean + 6σ approach

• Bear in mind that the volume administered in the eye is usually one or two drops (50µl)

• Field standard proposed based on actual data reviewed for example

- max 1000 particles/ml ≥10 µm - max 100 particles/ml ≥25 µm • This approach was welcomed but has not yet

been adopted by Ph. Eur Commission 24-Nov-15 28

Conclusion • Parenteral preparations should not contain

particles • Pharmacopoeial standards very important to

control particulate levels, particularly of sub-visible particles

• Important to have harmonised standards between Ph. Eur, JP and USP

• Tripartite agreement on prospective amendment to maintain the harmonisation taking into consideration new data available from new product types

24-Nov-15 29

Conclusion continued

• Particulate standards may be useful also in eye preparations

• Maybe a general information chapter on particulate contamination – visible and sub-visible particles would be a useful development in Ph. Eur.

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Thank you for your attention