S. Mathonet on behalf of EBE

CASSS CMC Strategy Forum – EBE satellite session – Sorrento – May 5, 2014

Industry Perspectives on Visible

Particle Requirements and Practices

– An overview of EBE position paper

Primary goal of the EBE position paper

• Problem statement: An acceptance criterion of ‘no’ or ‘free from’ or

“without” visible particles is recognised as totally unrealistic

• Define and justify « Practically Free from Visible Particles » as

acceptance criteria for products effectively free of visible particles

for biotech products (focus on recombinant antibodies)

• As exception, define and justify acceptance criteria for products

containing low level of protein particles

• Provide an insight into current industry practices and reach

consensus on minimum requirements and best practices for visual

inspection

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EBE position paper layout

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Position Paper Layout

1. Problem statement

2. Visual Inspection at end of DP manufacturing

3. QC sample testing

a. Release testing including discussion

on sampling plan and size

b. Stability testing including discussion

on sampling plan and size

c. Acceptance criteria and justification

Drug Products effectively free from particle

Drug Products containing low level of proteinaceous particles

4. Proteinaceous particle characterization

5. Patient safety

6. Continuous Process optimization and

Conclusion

Annexes

Inspector certification

Risk assessment and ranking of particle defects

Sampling Plans

Literature references

• Focus of the presentation:

Defining Practically Free from Visible

Particles - Guiding Principles

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Pharmaceutical development

Commercial formulation and process design

• Fulfilling multiple TPP goals in formulation design may

represent a challenge in achieving a formulation devoid of

protein particles

- e.g. sub-cutaneous liquid formulation with high concentration protein

solutions

pH, osmolality, viscosity, soluble aggregates, opalescence, coloration and

sub-visible/visible particles, syringeability / Injectability when TPP includes

delivery device

• It was however agreed in the EBE Visible Particle Sub-Group

discussion that visual appearance including visible particle

free formulation was a main objective for formulation design

• Evaluation of process holding times and processing conditions that

may bring stress to the protein including formation of protein

particles should be considered in process design

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Visual Inspection process

Fillling into container

100% Visual Inspection

Rejected Part of the batch

AQL Visual Inspection (statistical sampling)

Accepted Part

Pass

QC release Visual Inspection Small sample subset (leverage AQL results when justified)

Fail (1)

Visual Re- (3) Inspection 100% of accepted part

Batch rejection

Rejected Part of the batch

Number of repeat to be justified in Quality System

Batch release

QC Stability Visual Inspection Small sample subset

Investigation Mode/ Re-inspection

Batch rejection

Fail (2)

(1) Rare random occurrence of single source particle

(2) Obvious particle reflective of systemic failure

Pass

Non conformance investigations

Rejected Part of the batch

Periodic Trending of Visual Inspection data (Reevaluate what’s Normal and limits)

(3) As per company-specific QA procedures

100 % visual Inspection

• 100 % inspection is a unit operation after filling. It can be manual, semi-

automated or fully automated.

• Every filled units (100%) are visually inspected for critical, major and minor

defects including particles

• In 100% inspection, for products practically free of visible particles,

any unit with visible particle defect irrespective of its nature is

discarded. It applies to liquid and lyophilisate

• For liquid formulations, protein particles are typically sorted during

100% inspection not being differentiated from other particles

• Visible Particle Defect rate ((i.e. maximum visual defects in % of whole

batch filled) criteria should be in place as representative of the

commercial process

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100 % visual Inspection

• Inspection conditions defined in EP (and USP draft) monographs are:- 2,000-

3,750 lux- Black and white backgrounds- 5 sec viewing against each

background. The threshold of “visibility” depends on many parameters

and can range from ca. 50 to 400 μm, with different detection probability

• Detection of visible particles is a statistical process, in daily practice,

the detection limit very much depends on:

- Individual operator,

- Inspection system and Inspection time

- Morphology, number and refractive index of the particles, rheology and

opalescence of the solutions as well as other factors.

• Companies may use other, non-EP methods to improve the sensitivity or

ergonomics of the process i.e. use of aids such as magnifying glasses or

differences in lighting conditions or observation times and swirling procedures.

• These conditions may have a pronounced effect on reject rates.

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AQL Inspection

• AQL testing is done to confirm the quality of the product and to confirm the

efficiency of the 100% visual inspection to remove defective product.

• Inspectors should be independent from those that did the initial inspection

• Particle in solutions are at least a major defect in most companies.

Lowest Acceptable Quality Level applied across companies is 0.65%. If

AQL is exceeded, 100 % inspection may be repeated as per company specific

QA procedures

• Occasional random occurrence is an important concept for visible particle

defect.

- A batch may be passed if within the AQL criteria

- Any AQL failure may generate 100% re-inspection of the accepted part of the

batch and a repeat of AQL testing.

• Companies should define and justify number of repeat in their own quality

systems (usually not more than 2 cycles of re-inspection)

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AQL Inspection

• Manufacturers are expected to have calculated the capability of

the commercial fill / finish process and use this capability to set

alert / action limits for the whole defect rate compared to filled

units (batch size)

- When these alerts limits show special cause for variation in the process,

additional AQL samples may be required to provide additional

assurance of quality

• Any obvious visible defect issues with regards to nature of

particles and representing a systemic failure (insect wing, rust,

paint, hairs,…) will lead to an investigation/re-inspection

- The investigation should evaluate aseptic processing conditions and

potential for sterility breach, systematic failure may lead to batch reject

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QC Release Testing

• Option 1: Leverage AQL testing (Real Time Release Testing)

- QC Batch Release testing may take the AQL testing results into account

and can determine the AQL result as sufficient and appropriate to confirm

the specification of ‘practically free from visible particles’

e.g. for iv/sc liquid formulations in vials or prefilled syringes

- This approach requires that the AQL inspectors are trained to the same

level as QC and/or Manufacturing inspectors

- The competent authorities (GMP Inspectorate) may allow the AQL

testing as a release test, within scope of inspection during MAA or variation

review, as required

- Furthermore, by describing the RTRT approach on the drug product

specification, a product manufactured in a non-EU country without MRA

may have ‘relief’ from repeat testing on importation into the EU ?

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QC Release Testing

• Option 2 Separate QC testing

- Especially if destructive method is involved such as reconstitution

of a lyophilised powder, sample size considerations need to take

this fact into account

QC testing of a small subset of the batch (e.g. 20 units / justified

sample size) and acceptance criteria based on processing

capability and packaging component is sufficient

Reconstitution procedure should be carefully designed

- When visual inspection is required as part of QC testing for

liquid formulations, similar sample size considerations apply

as for lyophilisates

- When the integrity of the sample is not impacted by the testing

(non destructive), reuse of sample for other testing is

acceptable as long as the sample handling and testing conditions

are shown not to effect the product quality

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QC Release Testing (prefilled pen injectors)

• PFS may be inspected for visible particles, prior to assembly, if

container integrity during assembly is warranted, since

- the pre-filled primary container for the biologics cannot be easily

removed: e.g. the device assembly components lock the PFS inside

- the inspection window in a device might not always be fully adequate

for a visual inspection of particle and cannot be qualified for this use

- disassembly may impact the container closure integrity and create

other cosmetic defects such as scratching that could impair visual

inspection

• Similar proposal is recommended for other assembled biologics/

device combination products

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QC Stability Testing

• Different practices across companies

- For Practically free from visible particles, it is acceptable to test a sub-

set of samples (justified sample size) using EP / USP draft monographs

visual inspection method and acceptance criteria justified based on

product history (with e.g. random occurrence of single source particle)

- Some companies do not specify Visible Particle in shelf life specification but

visible particles are still monitored in stability storage with a semi-

quantitative assay

E.g. based against a set of standard vials containing defined level of particle

defect with different number of particles – presence of visible particles yes/no

plus particle count)

- FlowImaging replacement on visual inspection - hot debate!

Sensitivity (instrument based versus eye)

Influence of instrument setting/sample handling

Precision

Characterization or QC tool ?

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QC Stability Testing

• Same stability samples (for non-destructive testing of a liquid

product) may be used for all time-points tested or separate units are

inspected per timepoint

• Using the same stability samples provide an advantage being

able to monitor a possible increase / appearance of particles

over stability e.g. stemming from interactions of formulation and

primary packaging, protein particles etc.

• However, it must be confirmed that the inspection procedures

and related handling (e.g. temperature differences) do not

impact visual inspection results

• More discussion needed on stability testing in EBE Visible Particle

Topic Group!

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Particle Characterization during product

development or non-conformance investigations

• Identification of the origin of the particle(s), from the environment,

product, packaging components or process is required to support risk

management in control strategy and drive CAPA

• The identification of the whole particle population in a unit or even all

units present challenges

• Limited sample size (e.g., thickness, size, mass of a particle and/or number

of particles), changes to the chemical signature (e.g., by heat impact during

manufacture) and the destructive nature of certain analytical techniques

(“one shot on at the goal”) add to the challenge of particle identification

- A key challenge is isolation of particles, especially single particle around 150

micron. Some inherent protein particles are fragile to filtration and may permeate

the filter or even return back into solution.

• No agreement in the EBE Visible Particle Topic group yet on inherent,

intrinsic, extrinsic particle categorization

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Particle Characterization during product

development or non-conformance investigations

• A toolset of various (complementary) analytical techniques provides

the best opportunity to characterize particles, particularly protein

particles (Microscopic techniques, Mass spectrometry, FTIR,

Raman spectroscopy, SEM-EDX)

• The identification of visible particles is suggested to be

focused on individual investigations and not be considered for

routine or QC testing

- companies have succeeded however in setting a specification allowing

some level of protein particles that have been characterized and

assessed during clinical trials

Will be addressed in case studies

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Conclusion: Justification of « practically free »

acceptance criteria in Clinical/Commercial filings

• A suitable justification for the practically free from particles could

include a definition on the intent of the specification and a brief

outline of the manufacturing controls in place to control for visible

particles including the 100% inspection and AQL to ANSI/ASQ Z1.4

or ISO 2859-1 , equivalent standards or better testing

• A holistic approach to control might be taken from raw materials

through to finished product

• When particles detected under the practically free from particles

specification, trigger a non-conformance process, the level of non-

conformance and investigation route would depend on the

assessment of the particle (nature and frequency of occurrence).

• The product history for detection, identification and characterisation

of visible particles should be documented

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Acknowledgements

• Thanks to all EBE Visible Particle Topic group contributors

- Sharon Adderley, Manufacturing Science and Technology,

Analytical Science, Pfizer

- Patricia W. Cash, Analytical Biotechnology, MedImmune

- Stefan Esswein, NBE Analytical R&D, Abbvie

- Christof Finkler, Analytical Development & Quality Control,

Pharma Technical Development Biologics EU, F.Hoffmann-La

Roche Ltd, Basel, Switzerland

- Andrew Lennard, Regional Regulatory Affairs CMC, Amgen

- Georg Kallmeyer & Hanns-Christian Mahler, Pharmaceutical

Development&Supplies, Pharma Technical Development Biologics

EU, F.Hoffmann-La Roche Ltd, Basel, Switzerland

- Maryam Mazaheri, Analytical Biotechnology , Medimmune

- Klaus Wuchner, PDMS Analytical Development, Janssen R&D

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• Backup Slides

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Inspector Certification

• Effective inspector selection, training, and monitoring necessary

for a reliable and consistent visual inspection program

- Certification of visual acuity and technical expertise that includes the

ability to detect particulates in test panels

• An inspector must be able to detect a predefined amount of defects

(without detecting a maximum amount of “false positives”) in order to

be qualified. Inspector must be re-qualified in regular intervals

• Ideally, the same principle of training and monitoring shall be

applicable to all personnel performing visual inspection for

visible particles be it during manufacture as part of 100% manual

inspection, AQL testing, QC release and stability testing, QA

reserves/retention and product complaints

• Different company practice- This Annex still heavily discussed in the

EBE Visible Particle Topic Group !

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Inspector Certification

• Training Process for Inspector

- Introduction to general visual inspection method

Different company practices

- If a defect (incl. particle) library is available a demo of typical defects should be

performed

- Demo of visual inspection method by trainer

- Demo of sample handling and handling (e.g. agitation) method, according to

predefined SOP

- Introduction to defect categories as per predefined SOP

- Proficiency runs using appropriate test panels (qualification defect test set) for

the process and product, as many as required

- Independent Performance runs with defined acceptance criterion level

for particle defects Company specific

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Inspector Certification

• Maintenance and Monitoring of Visual Inspector

- A minimum of procedure review and assessment in regular intervals .

- A minimum of annual inspector assessment ; compliance to SOP and

ability to detect defects

- Eye exams must be performed in regular intervals

- Inspector must be re-qualified at regular intervals to be considered a

qualified visual inspector. •

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