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HIAC Liquidborne Particle Sampling: Compendial Methods

System Design

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Liquid Particle CountingApplications

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

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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

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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

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Definition of Particulate Contaminants

USP <788>:“Particulate matter in injections and parenteral infusions consists of

extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions.”

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

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Global Regulations: Particles in Liquids

USP

EP

JP

KP

ChP

HARMONIZED !!!

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Global Regulations: Particles in Liquids

USP <788>, EP 2.9.19, JP <6.07>, KP <52>

Primary method• Optical Particle Counter [OPC]

– Light Obscuration Counter

Secondary method• Optical microscope

– Subjective– Labor intensive– Requires more time to process samples

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Light Obscuration

Light Obscuration Sensors and system• also known as Light Extinction• also known as Light Blocking

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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

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Principles: Light Obscuration

Detector Output

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Detector Output

Principles: Light Obscuration

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Principles: Light Obscuration

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Alumino-silicate with K and Ti

Talc

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Sizing Particles by Microscope

Largest Dimension

d

Feret’s Diameter

d

Projected Area

d

Martin’s Diameter

Area A

Area B

d

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General Comments on Liquid Counting

Particle Counters Report Size But measure an Optical ResponseCommonly there is a difference in

reported size compared to microscope

Calibration Relates the Optical Signal to SizeDifference between calibration

material characteristics and “real world” particles

Projected Area

d

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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

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Verification:Count Standards

Works for JP calibration

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Verification:Count Standards

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Parenteral vs. Injectable

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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

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Challenges of Protein-based Products

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• End-user must be careful about excessive or aggressive shaking

or mixing in order to re-mix at time of use

Transparency of most proteineous entities• Refractive index• Lack of contrast

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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

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USP <787>

“When a product diluent is specified, e.g., for lyophilized solids or powders for parenteral use, the reconstitution or dilution must be performed with the appropriate amount of specified diluent. In this case the diluent itself must be tested to ensure that it is not a significant source of particles. Subtraction of the diluent count from the total count is not allowed. Eliminating gas bubbles is a key step, especially for protein injectable products that may entrain gas. Two methods are recommended: either allowing the product fluid to stand under ambient pressure or applying gentle (e.g., 75 Torr) vacuum. Sonication should be avoided. Once the samples have been degassed, they must be remixed gently to suspend all particles by mixing the contents of the sample gently but thoroughly by an appropriate means, e.g., slow swirling of the container by hand. Inversion to mix the product fluid is not recommended at any time.”

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Comparison: USP 788 and 787

USP <788> USP <787>

Applies to

All injectables, except:Veterinary

RadiopharmaceuticalsFiltered syringes

Therapeutic Protein Injections as defined in Biotechnology-

derived articles <1045>; natural source Therapeutic

Protein Injections

Pooled volume for dose forms under 25 mL Minimum 25 mL 1 to 25 mL

Number of containers(minimum) 10 “suitable number”

Agitation/mixingInversion 20 times

swirlingSwirling OKNo inversion

DegasSonication

SettlingNo sonication

Vacuum preferred

Maximum particle counts6000 per container at 10 µm600 per container at 25 µm

6000 per container at 10 µm600 per container at 25 µm

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HIAC Liquid Particle Counters

Example: HIAC 9703The industry standard liquid particle counter since 1997

USP <788> was written specifically around HIAC technology

Every major standards manufacturer uses the HIAC 9703

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HIAC Liquid Particle Counters

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• Ideal for R&D and other low

frequency, small sample volume applications

ReproducibilityRepeatability

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Patent Pending

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New Hardware: 9703+

Key featuresAuto stop for sensor elevator arm

Small vial holding clamp

Sample probe with reduced dead volume

Back-flush and forward flush from front panel

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Software: PharmSpec 3

Key new featuresCompendial test support continues

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

Uses Windows logon

Improved Report format

Improved Error Detection and Display

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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

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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

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New Sampling Probe

3 probes available

• 2 probes have not changed

¼” ID =1.2 ml tare volume

1/16” ID = 0.172 ml tare volume

• New small / short probe1/16” ID = 0.09 ml tare

volume

Enables the use of 1 ml of product for tests

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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

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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

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Part 11: Electronic Signature

Re-entry of password:

Stricter interpretation of 21CFR Part 11 electronic signature process….

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PHA

PHA enables• Troubleshooting• Secondary sizing

validation• Diagnostic

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HIAC 9703+ Flexibility

Interchangeable sampling probes, syringes, and sensorsEnsure you have one instrument to manage

all applicationsNow supports MC05 sub-micron sensorChange configuration with no impact to

instrument validation

Customized reportingCustomize the number of reviewers and

approvers for compendial test reportsAdd company logo, user-defined descriptors

Customized test recipesProcedure Builder enables the development

of unique test recipes for your applicationCopy a recipe and make the changes!

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HIAC Liquidborne Particle Sampling:

Compendial Methods and System Design