Liquidborne particle counting using light obscuration and light scattering methods
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Liquidborne Particle Counting using Light Obscuration and Light Scattering Methods. What has been. Focus has been on injectable liquids Possibility to block capillaries and arteries Red Blood cells are about 5 µm Capillary (5 to 10 µm) Large veins (10 to 50 µm)

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Liquidborne Particle Counting using Light Obscuration and Light Scattering Methods

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Liquidborne particle counting using light obscuration and light scattering methods

Liquidborne Particle Counting using Light Obscuration and Light Scattering Methods


What has been

What has been . . .

Focus has been on injectable liquids

  • Possibility to block capillaries and arteries

    • Red Blood cells are about 5 µm

    • Capillary (5 to 10 µm)

    • Large veins (10 to 50 µm)

  • Threat of microbial infection

  • Allergic reaction to foreign substances


Definition of particulate contaminants

Definition of Particulate Contaminants

Unwanted insoluble matter that exist as “randomly-sourced extraneous substances”

  • Excludes homogeneous monotonic materials that exist as a precipitate or suspension

  • i.e. colloids, drug degradation or otherwise derived from a defined source and can be analyzed by chemical means

    Regarded as “contamination” and “adulteration” under Food and Drug Act

  • the chemical composition of the particulate is varied, and

    would not be declared on the label

    • Examples: bits of paper fiber, fragments of filler material, etc


Liquid particle counting applications

Liquid Particle Counting Applications

Final Product Testing – USP <788>

  • SVP or SVI (Small Volume Parenteral/Injectable)

    • Ampoules, Vials

  • LVP or LVI (Large Volume Parenteral/Injectable)

    • IV (Intravenous) solutions

      Process contamination studies

      Decomposition studies (stability)

      DI or WFI Water

      Precision Cleaning – Medical Devices

  • Aqueous

  • Other Chemicals


Other applications for particle counting

Other Applications for Particle Counting

Medical Devices

  • Cleanliness of manufacturing environment

  • Cleanliness of device before implantation

    • pacemakers, stents, artificial arteries

  • Cleanliness of reclaimed devices

    Design of particulate-based medicines

  • Inhalation therapies

  • Intentional occlusion of blood flow to cancers

  • Time-based dosages

  • Transdermal absorption


Global regulations particles in liquids

Global Regulations: Particles in Liquids

USP <788>, EP 2.9.19, JP XV, KP, CP

Primary method

  • Optical Particle Counter [OPC]

    • Light Obscuration Counter

      Secondary method

  • Optical microscope

    • Subjective

    • Labor intensive

    • Requires more time to process samples


Proposed usp 787 usp 1787

Proposed: USP 787, USP 1787

USP <787>

Under discussion

Focused on reducing necessary test volumes due to concerns of biotechnology manufacturers of cost for test

Expensive and often very small dose factory

  • for example: 500 uL pre-filled syringe


Proposed usp 787 usp 17871

Proposed: USP 787, USP 1787

USP <787>

Primary method ?

  • Optical Particle Counter [OPC]

    • Light Obscuration Counter

      Secondary method ?

  • Optical microscope

    • Subjective

    • Labor intensive

    • Requires more time to process samples


Proposed usp 787 usp 17872

Proposed: USP 787, USP 1787

USP <787>

Small sample volume

- 1 mL ??

Concerns with variability

- within production lots

- in analytical methods


Optical particle counter

Optical Particle Counter

Optical Instrument

  • Must move fluid through sensor

  • Can quantify particles from 100 nm to 5000 µm

  • Counts particles individually (one at a time)

  • Cannot tell you composition

  • But results are immediate


Many shapes and sizes

Many shapes and sizes

Talc

Alumino-silicate with K and Ti


Sizing particles by microscope

Sizing Particles by Microscope

Martin’s Diameter

Largest Dimension

Area A

d

d

Area B

Projected Area

Ferret’s Diameter

d

d


Challenges of protein based products

Challenges of Protein-based Products

Handling can change material !!!

  • Agitation

  • Heat and Light

  • Contaminates

  • Container: Vials versus syringes/cartridges

  • Shear forces

    Key concern is Aggregation

  • Reduction of native form (impacts efficacy)

  • Introduction of homogeneous aggregates

  • Introduction of heterogeneous aggregates


Challenges of protein based products1

Challenges of Protein-based Products

Transparency of most proteineous entities

  • Refractive index

  • NIST working on calibration material

    Not “contamination” but instead a shift from native form

  • Not a solution as with small-molecule therapeutics

  • Formation of quaternary structures [dimers, etc.]

  • Protein complexes

    Reconstitution of lyophilized product


Refractive index

Refractive Index

Key is the ability to distinguish between the particle and the surrounding fluid

- needs to be great enough

Optical response is proportional to comparative index


Refractive index1

Refractive Index

Key is the ability to distinguish between the particle and the surrounding fluid

- needs to be great enough

Optical response is proportional to comparative index


Refractive index2

Refractive Index

NIST working on protein-like calibration material

  • Probably 2 years away

  • Exploring 2 methods of manufacture

  • Need thread-like material

  • Indices near water

  • Stable over reasonable period


Ii sample handling

II. Sample Handling


Settling agitation

Settling/Agitation

Entrained gas

- sonication probably not ideal with protein structures

- light vacuum seems to work OK

Settling

Limits collection of particles

- especially of greater mass

- dependent on time and viscosity

- improved collection with slanted containers


Consistency of sample characteristics

Consistency of sample characteristics

Temperature

Settling

Probe position


Issues with sampling particles in liquids

Issues with Sampling Particles in Liquids

Sampling Errors Account for most problems

Accidental Contamination or Alteration by Technician

3. Sample Handling

Aggregation

Settling

Cavitation

2. Sample Preparation

Contamination

- Particles

- Gases

- Liquids

1. System Preparation

Initial Cleanliness

Calibration


Sizing particles by microscope1

Sizing Particles by Microscope

Martin’s Diameter

Largest Dimension

Area A

d

d

Area B

Projected Area

Ferret’s Diameter

d

d


Hiac liquid particle counters

HIAC Liquid Particle Counters

Example: HIAC 9703

  • The industry standard liquid particle counter since 1997

  • USP <788> was written specifically around HIAC technology

  • Every major manufacturer of particle calibration standards uses the HIAC 9703


Hiac liquid particle counters1

HIAC Liquid Particle Counters

Example: HIAC 9703+

  • Improved sample mounting method for small vials or containers

  • Detection of usual conditions such as bubbles or contamination

  • Proven syringe sampler

  • SVI and LVI sampling

  • Addresses non-compendial applications, e.g. R&D and other low frequency, small sample volume applications

  • Reproducibility

  • Repeatability


Detection ranges

Detection Ranges

0.1µm

1µm

10µm

100µm

Light Obscuration

Light Scattering

nm


Light obscuration

Light Obscuration

Light Obscuration Sensors and system

  • also known as Light Extinction

  • also known as Light Blocking


Principles light obscuration

Detector Output

Principles: Light Obscuration


Principles light obscuration1

Detector Output

Principles: Light Obscuration


Principles light obscuration2

Principles: Light Obscuration


Particle detection

Particle Detection

Like an air particle counter, the larger the particle, the larger the pulse that is created


Principles light scattering

Principles: Light Scattering

Detector Output

Detector

Light Trap

Laser Diode

Mirror


Principles light scattering1

Principles: Light Scattering

Detector

Particle

Light Trap

Laser Diode

Mirror


Advantages light scattering

Advantages: Light Scattering

Good sensitivity from 0,1µm to 50µm

Wide range of sample concentration

Good rejection of false counts

High sample flow rates


Disadvantages light scattering

Disadvantages: Light Scattering

More complicated construction = higher cost

Characteristics of particle surface (shiny, color) affect response


Effect of colors and surfaces on light scattering

Dark

Light

Shiny

Effect of colors and surfaces on Light Scattering


Liquidborne particle counting using light obscuration and light scattering methods

Talc

Alumino-silicate with K and Ti


Sizing particles by microscope2

Martin’s Diameter

Largest Dimension

Area A

d

d

Area B

Projected Area

Ferret’s Diameter

d

d

Sizing Particles by Microscope


General comments on liquid counting

General Comments on Liquid Counting

Particle Counters Report Size

But measure an Optical Response

Difference in reported size compared to microscope

Calibration Relates the Optical Signal to Size

Difference between calibration material characteristics and “real world” particles

Projected Area

d


General comments on liquid counting1

General Comments on Liquid Counting

Particle Counters Report Size

But measure an Optical Response

Differences in reported size compared to microscope

Calibration Relates the Optical Signal to Size

Difference between calibration material characteristics and “real world” particles


Lo results versus ls results

LO results versus LS results

Light Obscuration [LO]

  • Good immunity to variations of surface and morphology

  • Very stable

  • Limit of quantitation circa 1.2 – 1.3 microns

    Light Scattering [LS]

    Results affected by surface characteristics and coloring

    Good stability

    Limit of quantitation sub-micron

    Problem can occur in the attempt to correlate results of these two methods above 1 micron


System preparation

System Preparation

2-step Verification - optional:

  • Run 2 test solutions

    • Blank (“particle-free” water)

    • Aqueous solution containing known counts

      at 10 µm or 15 µm

      In the range of 1000 to 3000 counts per mL

  • Frequency – based on risk analysis

    • Each morning

    • Shift change

    • Change of operator

    • Other interval


System preparation1

System Preparation

Check for bubbles in sample lines and syringe

  • Affects flow rate and calibration

    Verify correct calibration curve installed

  • Different flow rates for same sensor

  • Change of syringe size

  • Some companies have multiple sensors

    Verify calibration is current

  • Sensor resolution and response curve

  • IST tests conducted [USP, JP]


System preparation2

System Preparation

Instrument Standardization Tests [IST]

  • Five tests of system

    • Volume accuracy

    • Flow rate accuracy

    • Calibration of sensor

    • Resolution

    • Count accuracy

  • Required by USP and JP but not EP

    • USP <788> 31

      “…at intervals of not more than six months.”

    • JP <24>

      “…at least once a year.”


Sample preparation

Sample Preparation

Removing residue of previous sample

  • If previous sample contained particles, may be good plan to run a “particle-free” blank before the next sample

  • Use liquid that is compatible with sample fluid

    • An aqueous blank could trigger false counts in an oil-based sample by causing immiscible droplets

    • Potential residue from previous sample can cause change of counts

      Data from first run of series is often discarded


Sample preparation1

Sample Preparation

Contamination

  • Particles

  • Gases

  • Liquids


Sample preparation2

Sample Preparation

True Particle Sources

  • Residue on glassware and equipment

  • Ambient air

  • Paper dust

  • Glass

  • Diluent

  • Residue from previous sample

  • Colloidal suspensions

    False Particle Sources

  • RF signals or other electronic interference

  • Bubbles from entrained gases


Sample preparation3

Sample Preparation

Work in controlled environment

Use particle-free gloves

Let water flow for 200 mL or more after opening a valve / tap

  • Opening / closing valve generates particles

    Wipe the outside of containers before sampling

  • Particles on surface of vials or ampoules

    Open vials and ampoules away from beaker or flask

  • Particles from activity can fall into open container

  • Wash outside of containers to reduce potential particle source


Degassing sample

Degassing sample

Three common methods

  • Allowing to stand in ambient air

    Risk of large particles settling

  • Sonification [ultrasound]

    80 to 120 watts [USP <788>]

    30 seconds [USP <788>]

  • Vacuum

    Bell jar or dessicator

    0.6 – 0.8 atmospheres for 2 to 10 minutes


Sample preparation4

Sample Preparation

Possibility of decreasing true particle counts

  • Settling

  • Lack of agitation

  • Position of probe in sample vessel

  • Remaining material from previous sample run

    • Sample with lower counts

    • Blank


Sample handling

Sample Handling

Aggregation

Settling

Entrained gases


Sample handling1

Sample Handling

Aggregation

  • Samples held over time or at extremes of temperature can develop aggregates of smaller particles

  • Exposure to light can also trigger this reaction

  • Sub-micron particles can thus add to particle counts above 10 µm

  • Suggestion:

    • Profile counts under 10 µm [e.g. at 2 or 5 µm] in addition to standard count sizes at 10 and 25 µm


Sample handling2

Sample Handling

Settling

  • Undercounting caused by

    • Gravitational settling

    • Failure to suspend particulate matter adhering to walls or stopper of container

  • Standards have recommended procedure for agitation

    • Multiple inversions of original container before decanting

    • Constant motion of liquid during sampling

      “Gently stir the contents of the container by hand-swirling or by mechanical means…” USP <788>


Optical particle counter1

Optical Particle Counter

Instrument & sensor

  • Must move fluid through sensor

  • Can quantify particles from 100 nm to 5000 µm

  • Counts particles individually (one at a time)

  • Cannot tell you composition

  • But results are immediate


Questions

Questions?


Liquidborne particle counting using light obscuration and light scattering methods

Patent Pending


New hardware 9703

New Hardware: 9703+

Key features

Auto stop for sensor elevator arm

Small vial holding clamp

Sample probe with reduced dead volume

Back-flush and forward flush from front panel

Supports MC-05 sensor (0.5 micron sensitivity)


Software pharmspec 3

Software: PharmSpec 3

Key new features

Compendial test support continues

USP, EP, JP, KP looks same as previous PharmSpec versions

Uses same log on as for Windows

Improved Report format

Improved Error Detection and Display


Still the hiac 9703 you know and trust only better

Still the HIAC 9703 you know and trust – only better!

Syringes

1 ml, 10 ml, 25 ml

Flow rate settings

10 to 100 ml

Sensors

MC-05 is added

Sampling Probes

added shorter small-bore probe

Instrument size / shape

50%+ of instruments are placed in laminar flow cabinets.

Smooth, curved surfaces create less turbulence for the air flow


Easier faster and confident sampling

Easier, Faster and Confident Sampling

Use less sample, save valuable time - protect your investment

Small vial clamp ensures that sample does not spill during testing

Probe needle safety switch prevents probe damage

New small needle probe with industry’s smallest tare volume


Easier faster and confident sampling1

Easier, Faster and Confident Sampling

Reduce uncertainty from data anomalies

Bubble alarm notification

Contamination alarm notification

Advanced notification when service or calibration is due

Invalid configuration notification


Hiac just got easier

HIAC just got easier!

Less time needed for clean-up

Automated flushing and cleaning routines

Push a button, walk away and return to a clean sensor

Export your data with ease

Select one, several or all of your historical data records with our batch export utility

Select PDF, Word, Excel, or text files

Save time with electronic signature

Stricter interpretation of 21CFR Part 11 electronic signature process…. WITHOUT more manual inputs

Remembers user Login ID


Hiac 9703 flexibility

HIAC 9703+ Flexibility

Interchangeable sampling probes, syringes, and sensors

Ensure you have one instrument to manage all applications

Now supports MC05 sub-micron sensor

Change configuration with no impact to instrument validation

Customized reporting

Customize the number of reviewers and approvers for compendial test reports

Add company logo, user-defined descriptors

Customized test recipes

Procedure Builder enables the development of unique test recipes for your application

Enables testing to marketing license-specific applications


New sampling probe

New Sampling Probe

3 probes available

Tare

¼” ID =1.2 ml tare volume

1/16” ID = 0.172 ml tare volume

New small / short probe

1/16” ID = 0.09 ml tare volume

Tests can be performed on 1 ml of product!


Small vial clamp

Small Vial Clamp

Small Vial Clamp Platform

Can be retrofitted

Can be removed

Ease of Use

Use one hand to compress lever arms

Use other hand to place sample in central location

Decompress hand

Clamp auto-centers and holds sample container


Docking module

Docking Module

Docking Module

Enables removal/disabling of the stir bar mechanism

Enables field installation of small vial clamp outside of the laminar flow cabinet

Avoid potential of re-qualification that can occur if instrument is moved

Future developments to expand 9703 applications


Sampling safety switch

Sampling Safety Switch

Sampling safety switch

Ensures the sampling probe does not crash (and bend or break) into the docking module

Ensures the probe does crash into or tip the sample container


Liquidborne particle counting using light obscuration and light scattering methods1

Liquidborne Particle Counting using Light Obscuration and Light Scattering Methods


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