Particle Lifecycle Management

Atanas Koulov
Chief Scientific Officer
Clear Solutions Laboratories
atanas.koulov@clearsolutions-labs.com
Fevereiro 2, 2024, 14:00

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Particle Life Cycle Management

Prevention

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Control Strategy for Therapeutic
Products
1. Control System
a. In-process control
b. Release testing
c. Stability testing

2. Monitoring
a. Periodic or continuous monitoring (action limits)

3. Additional characterization
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Particle Control Strategy
1. Control System
a. 100% VI (part of the manufacturing process)
b. Release testing (e.g. AQL)
c. Stability testing

2. Monitoring
a. Periodic or continuous monitoring (action limits)

3. Additional characterization
a. Particle investigations and assessments; facility libraries

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1a. 100% Visual Inspection -
inspection methods

● Compendial chapters
(USP<790>/ EP 2.9.20.)
● Compendial methods are considered validated, BUT
suitability for the product needs to be assessed
● Depending on the attributes of the product,
the inspection method can be enhanced

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1a. 100% Visual Inspection -
inspection methods

● Inspection method enhancements for e.g. Difficult to

Inspect Products (DIPs):
○ increased light intensity
○ increased duration of inspection
○ others

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1a. 100% Visual Inspection -
inspection methods
● Different approaches, depending on the batch size and
product attributes:
○ MVI
○ SAVI
○ AVI
MVI always remains the basis on which automated
approaches can build on

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1a. 100% Visual Inspection -
qualification

● VI defect sets are the most important tool used

to qualify VI operations
○ Training and qualification of inspectors
○ Training and qualification of AVI systems
○ Benchmarking and harmonization of performance

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1a. 100% Visual Inspection - VI defect
test sets

● Product-specific vs. “generic”

● Product-specific defect sets are preferred (especially
for commercial products)
● It may be possible to set up test sets for a group
products (based on product attributes, PP, etc.)

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1a. 100% Visual Inspection -
Threshold studies (Knapp
methodology)

● A multifunctional tool:
○ Define Detectability (PoD) for different particle types/ sizes
○ Qualify inspectors
○ Basis for the design of different test sets
■ introduction/ training
■ testing/ qualification
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1a. 100% Visual Inspection -
Inspector qualification

● Training
○ setting up solid training programs is a critical success
factor (see PDA training courses)

● Visual acuity
● Inspector qualification - testing - challenge sets

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Particle Control Strategy
1. Control System
a. 100% VI (part of the manufacturing process)
b. Release testing (e.g. AQL)
c. Stability testing

2. Monitoring
a. Periodic or continuous monitoring (action limits)

3. Additional characterization
a. Particle investigations and assessments; facility libraries

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1b. Release testing

● AQL results can be used for batch release

● Alternative: QC testing (e.g. for lyo)
○ Challenges:
■ sample size typically not statistically powered
■ Alignment of practices across units is critical

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1c. Stability testing

● Very different goals of VI, depending on the context:

○ 100% VI - remove defective units from the batch
○ AQL - quality assurance tool; can be used for batch
release
○ Stability - detect potential product instability over long-
term storage

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1c. Stability testing

● Additional considerations:
○ Potential intrinsic (typical product-related) particles are
mostly irrelevant
○ How do we qualify inspectors for detecting “inherent”
particles?

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2. Monitoring

● Continuous/ periodic monitoring is essential for

maintaining quality
● Basis for continuous improvement programs
(see 3.)

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2. Monitoring

● Facility particle libraries:

○ give an idea of the typical-process related
(intrinsic) particles that can may occur in the given
facility
○ provide a knowledge base for carrying out
investigations
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2. Monitoring

● Trending programs (process + procedures)

○ give an idea of the typical-process related
(intrinsic) particles that can be expected to occur in
the given facility
○ Essential tool for continuous improvement
programs and harmonization projects

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3. Additional Particle Characterization

Critically important tool for:

● Investigational support - root cause investigations
● Building facility libraries

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3. Additional Particle Characterization
● Thorough characterization is essential for
understanding particle profile in the given facility
● The main levels of characterization:
○ Visual characterization by the operator
○ Visual characterization by an expert
○ Microscopic and micro-spectroscopic characterization
(requires a specialized lab/ facility - internal or with a
reliable external partner)

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3. Additional Particle Characterization
● Micro-spectroscopic particle characterization
● Requires:
○ Special instrumentation
■ Light microscopy
■ FTIR/ Raman
■ SEM-EDX/ LIBS
■ MS

○ Expertise:
■ Technical
■ Understanding of pharmaceutical manufacturing

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Continuous Improvement - important
components

● Trending/ monitoring - understand the particle

ingress (contribution of process, equipment and
procedures in the facility)
● Supplier selection and improvements
● Incoming goods control
● Benchmarking
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Prevention

● Product development - good development is the

best guarantee for product quality:
○ Formulation and container closure system (delivery)
○ Compatibility with materials
○ Process development

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Prevention

● Supplier assessment/ qualification

● Process capability assessments
○ Establish a baseline - use water runs/ medial fills
● Manufacturing process and procedures design
○ Use materials and processes that are less likely to
shed particles

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Prevention
● Harmonization of practices across multiple sites:
○ VI
○ Qualification:
■ requirements
■ test set composition

○ Investigations - technical and quality aspects

○ Remediation and risk mitigation measures

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Particle Life Cycle Management

Prevention

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