United State Pharmacopeia

Particle Determination:
Guidance for Parenteral Products
Presented by: Roy T Cherris, Managing Partner
Bridge Associates International, LLC
Member of the USP Visual Inspection Expert Panel

Presentation acknowledgement:
Desmond G. Hunt, M.S., Ph.D.
USP Sr. Scientific Liaison
 <788> Particulate Matter in Injections

 Two Methods with 10μm and 25μm size thresholds for

counting
• Primary method is an optical particle counter
– Light Obscuration (LO)
 Secondary method is filtration, membrane capture, light
microscopy count
• Membrane Microscopy (MM)

Method 1 – LO Method 2 - Microscope

Parenteral  10 m  25 m  10 m  25 m
Volume

SVI 100 mL 6000 (per 600 (per 3000 (per 300 (per
and lower container) container) container) container)

LVI above 100 25 (per mL) 3 (per mL) 12 (per mL) 2 (per mL)
mL
 <788> Particulate Matter in Injections
Revision Topics
 Particulate Matter Type: Inherent (part of the formulation)
• Protein agglomerates, Suspension, Microparticles
 New specification for Large Volume Parenteral (LVP)
• Difference between the Small Volume Parenteral (SVP) and LVP
specifications
Method 1 – LO Method 2 - Microscope
Parenteral Volume  10 m  25 m  10 m  25 m
SVP 100 mL and lower 6000 (per 600 (per 3000 (per 300 (per
container) container) container) container)
LVP above 100 mL 25 (per mL) 3 (per mL) 12 (per mL) 2 (per mL)

• Potential for a greater total particle Product (mL)

25/3 per mL
Current Limit/Unit
load in the LVP case. 100mL 2500/300
̶ Example, at 240mL LVP could exceed 125mL 3125/375
the SVP ≥10µm limit and be 150mL 3750/450
acceptable based on current LVI 200mL 5000/600
240mL 6000/720
limits.
250mL 6250/750
• A ceiling (container-based) limit for 500mL 12500/1500
LVP’s similar to that of SVP’s 1000mL 25000/3000
 <788> Particulate Matter in Injections

Revision Topics
 Eliminating requirement for pooling SVP samples for the
Microscopic Test
• The Microscopic Test currently requires pooling the contents of 10 or
more containers for SVP’s less than 25 mL
̶ Similar to Method 1
• This requirement is not necessary for the Microscopic Test
 Alternative sample preparation
 Smaller sampling volumes
 Alternate Methods, e.g. Flow Imaging Analysis
 More guidance on for products that are not amenable to
<788> Testing
• Suspension, Microparticles, etc.
 <1788> Methods for the Determination of Particulate
Matter in Injections and Ophthalmic Solutions

 Provides LO calibration and control guidance removed from

<788> after harmonization
• Instrument Standardization Tests
̶ Flow Rate
̶ Volume Accuracy
̶ Calibration
̶ Sensor Resolution
̶ Particle Counting Accuracy
 Provides LO calibration and control guidance removed from
<788> after harmonization
 Provides microscopy setup and counting guidance
 Provides discussion regarding pharmaceutical development
practices
 <787> Subvisible Particulate Matter in Therapeutic
Protein Injection

Scope and Purpose

 This chapter can be used as an alternative to USP general
chapter Particulate Matter in Injections <788>.
 It specifically addresses therapeutic protein injections and
related preparations, allowing use of:
• Smaller test product volumes
• Smaller test aliquots to determine particulate matter content
• Sample-handling instructions that take into account the issues
associated with the analysis of these materials.
 <787> Subvisible Particulate Matter in Therapeutic
Protein Injection
Highlights
 Dilution is allowed as long as the diluent and methods
are demonstrated to be appropriate and the smallest
level of dilution that allows for reproducible testing is
used
 Specifications same as <788>
– Limits for > 10 and > 25 µm
– All sections written assuming measurements
below10 µm
 Products that are used with a final filter during
administration (in-line) are exempt from these
requirements, providing that scientific data are available
to justify the exemption
 <1787> Measurement of Subvisible Particulate
Matter in Therapeutic Protein Injections

Highlights
 Describes the strengths and limitations of specific methods for
characterizing protein particle populations between 2 and 100
µm
 Methods that allow assessment of characteristics of the inherent
protein aggregates including morphology, conformation,
reversibility/dissociation, and covalent modification
 Since the monitoring of the sub-10µm population may be an
important product quality parameter, collection of data in the 2-10
µm range ( e.g. 2-5 µm and 5-10 µm) is recommended
 Focuses on the enumeration, characterization, and when
possible, identification of inherent particles, distinguishing them
from extrinsic and intrinsic particles
 <1787> Methodologies Useful in Measuring
Properties of Subvisible Particles
Section I: Size and Distribution
Technique Principle of Operation Range
Light obscuration
The size of the particle in the product
fluid is determined by the amount of light
that it blocks when passing between the
source and the detector. 1–300 µm
Electrical sensing zone
(Coulter)
The size of the particle in the product
fluid or selected electrolyte is measured
in terms of the change in resistance as
the particle passes through a micro-
channel (orifice). 0.4–1600 µm
Laser diffraction
The size of the particles in product fluid
or dilution is determined by measuring
the angle of the scattered light. 0.1–3500 µm
 <1787> Methodologies Useful in Measuring
Properties of Subvisible Particles

Section II: Size and Morphology

Technique Principle of Operation Range
Light microscopy
<776>
Photon imaging of substances directly
in product fluids or mounts, or of
isolated specimens on substrates 0.3 µm to 1 mm
Flow imaging analysis
Digital image capture of the particles'
magnified image in streaming product 0.7–100 µm for size
fluid, revealing size, shape, and distribution; 4–100 µm
optical properties for morphology
Electron microscopy (EM):
Scanning EM, scanning Electron imaging of specimen isolates
transmission EM, and on substrates. A high vacuum or near-
transmission EM <1181> ambient pressure is required. Angstroms to mm
 <1787> Methodologies Useful in Measuring
Properties of Subvisible Particles

Section III: Characterization

Technique Principle of Operation Range
Fourier Transform Infrared (FTIR)
microspectroscopy <197> Photon imaging of isolated specimens on
substrates utilizing mid-IR spectral detection 10 µm to 1 mm
Dispersive-Raman microspectroscopy
Photon imaging of isolated specimens on
<1120>
substrates, or in product fluids or fluid mounts
utilizing Raman shift detection 0.5 µm to 1 mm
Electron microscopy (EM) with
energy-dispersive X-ray spectrometry
X-ray photon emission from specimens energized Å to mm for imaging; 1 µm to 1
(EDX) <1181>
by a focused electron beam mm for elemental composition
Electron microscopy (EM) with
Inelastic scattering from specimens energized by Å to mm for imaging; 0.5 µm to
electron energy loss spectroscopy
a focused e-beam; e-loss is characteristic of the 1 mm for elemental
(EELS)
source element; complementary to EDS composition
Time of Flight Secondary Ion Mass
Spectrometer (TOF-SIMS) Identification of particles according to their mass
spectral profile µm to near mm
 Stimuli Article: PF 42 (5) Sept 2016

Analytical Gaps and Challenges for Particles in the

Submicrometer Size Domain

Scott Aldrich, Shawn Cao, Andrea Hawe, Desmond Hunt, Dean

Ripple, Satish K. Singh

ABSTRACT This Stimuli article provides a technical discussion of

the available technologies for submicrometer particle analysis,
including consideration of the advantages, disadvantages, and
technical gaps for each application. These methods can be used in
the characterization of different protein aggregates as well as other
types of particles in this size range. Changes are occurring rapidly
in this field, so the Stimuli article and discussions focus on
measurement principles and comparisons rather than specific
instruments.
Visible Particulate
 <1> Injections and Implanted Drug Products
(Parenterals) ─ Product Quality Tests

 Foreign and Particulate Matter

Each final container of all parenteral preparations
shall be inspected to the extent possible for the
presence of observable foreign and particulate matter
(hereafter termed “visible particulates”) in its contents.
The inspection process shall be designed and
qualified to ensure that every lot of parenteral
preparations is essentially free from visible
particulates Visible Particulates in Injections <790>.
 <790> Visible Particulates in Injections

 Inspection conditions defined

• Harmonized with Ph. Eur.
• 2,000-3,750 lux
• Black and white backgrounds
• No magnification
• 5 sec viewing against each background
• Swirl and/or invert sample
 Applies to Extrinsic and Intrinsic particles
 Inherent particles addressed in individual
monographs or approved regulatory filings
 <790> Visible Particulates in Injections

Acceptance Criteria
 At Time of Batch Release
• 100% inspection followed by acceptance sampling
• ANSI/ASQ Z1.4-2003 or ISO 2859
• AQL= 0.65%
• Alternate and equivalent plans acceptable
 For Product in Distribution
• n = 20, a = 0
• AQL= 0.26%
 <790> Visible Particulates in Injections

Other Considerations
 A smaller sample (such as the Special sampling plans in
the standards) is appropriate for destructive testing of
powders and suspensions
 This chapter does not add a new requirement for stability
testing
 Alternative light sources such as LEDs are acceptable
 The light intensity range stated is intended to establish a
lower limit of 2,000 lux, but it may be appropriate to
inspect at levels above 3,750 lux
 Alternative methods and conditions are permitted, but
should be shown to be comparable or better in
performance
 <1790> Visual Inspection of Injections

 Draft Information Chapter

• Published for comment in PF 41(1) January 2014
• Published for comment in PF 42 (6) December 2015
• Target Official Date: May 1, 2017
 Contents
• Patient Risk
• Typical Inspection Process Flow
• Elements of a good inspection process
• Inspection Lifecycle / Continuous Improvement
• Interpretation of Inspection Results
• Inspection Methods and Technologies
• Qualification and Validation of Inspection Processes
 <1790> Visual Inspection of Injections

 Scope
• Inspection for visible particles in filled, sealed
containers
• Applicable to detection and removal of other visible
defects e.g. container integrity
• Primary focus is manual inspection methods, but semi-
automated and automated methods are discussed
 <1790> Visual Inspection of Injections

 Typical Process Flow

Accepted
Units Acceptance
Filling 100% Sampling and Packaging
Inspection Testing

Rejected
Units

Analyze and Supplemental

Trend Rejects Testing
 <1790> Visual Inspection of Injections

Acceptance Sampling
 ANSI/ASQ Z1.4 Sampling Plans
• General Normal Level II
• Recommends Tightened Plans when atypical results are
observed
 Typical AQL Values
• Critical 0.010-0.10%
• Major 0.10-0.65%
• Minor 1.0-4.0%
 <1790> Visual Inspection of Injections

Remediation and Alternative Practices

 Re-inspection
• Repeat of 100% inspection after failure to meet acceptance
criteria
 Two-Stage Inspection
• First stage inspection (often automated) set to accept only
good product. Those of uncertain status are separated from
the batch and inspected by another method (often manual).
Those determined to be acceptable by the second
inspection are returned to the batch
• Used to address high false reject rates which can occur with
automated inspection systems and certain product
formulations and package types
 <1790> Visual Inspection of Injections

Preventions
 Inspection Lifecycle
• Continuous Process Improvement
 Robust Design
 Common Sources of Intrinsic Particles
• Formulation
• Packaging Components
• Processing
 Trending
• Establishing Alert and Action Levels
• Periodic review and update
 <1790> Visual Inspection of Injections

Interpretation
 Defect Classification
• Critical / Major / Minor
• Extrinsic / Intrinsic / Inherent
 Unique Product Considerations
• Lyophilized Products
• Powders
• Suspensions
• Emulsions
• Amber Containers
• Translucent Plastic Containers
• Large-volume Containers
• Combination Products
 <1790> Visual Inspection of Injections

Methods and Technologies

 Manual Visual Inspection (MVI)
• Critical Process Parameters
̶ Light intensity
̶ Background and contrast
̶ Inspection rate
̶ Container handling and movement
 Semi-Automated Visual Inspection
• Critical Process Parameters
̶ See MVI
̶ Machine parameters
• Spin speed
• Rotation rate
 <1790> Visual Inspection of Injections

Methods and Technologies

 Automated Visual Inspection (AVI)
• Light Obscuration Methods
• Imaging Methods
• Other Technologies
̶ Container Integrity / Leak Detection
̶ X-ray
 <1790> Visual Inspection of Injections

Qualification and Validation

 Standards
• Preparation
• Particle Types
• Defect Rates
• Test Sets
 Training and Qualification of Human Inspectors
• Qualification Requirements
• Requalification
Plastic Components and
Systems Used to
Manufacturer
Pharmaceutical Drug
Product
 USP Chapters Related to Plastic Materials and Systems:
Vision

USP <661.2> USP <1663>

Extractables
Packaging
<87> Biological
Reactivity In Vitro USP <1664>
Leachables
<88> Biological
USP <1665>
Reactivity In Vivo
USP <661.1> Toxicological
Assessment
Materials

USP <661.4> USP <661.3>

Devices Manufacturing
Systems
 <661.3> Plastic Components and Systems Used to
Manufacturer Pharmaceutical Drug Product

Objective
1. To provide tests and specifications for the characterization of
plastic materials so that plastic materials used in
manufacturing can be rationally selected for use and so that
the selection can be justified, and
2. To provide tests and specifications for the safety qualification of
manufacturing, packaging and delivery systems (or
components thereof).
Scope
The qualification of plastic components used in the manufacture
of both pharmaceutical and biopharmaceutical APIs and DPs.
• Chapter is applicable solely to those components that involve
liquid process streams and process intermediates that are
expected to have some degree of interaction with liquids.
 <661.3> Plastic Components and Systems Used to
Manufacturer Pharmaceutical Drug Product

Scope
 The qualification of plastic components used in the
manufacture of both pharmaceutical and biopharmaceutical
APIs and DPs
 Applicable solely to those components that involve liquid
process streams and process intermediates that are expected
to have some degree of interaction with liquids
 Single-use systems (SUS) and multiple-use systems (MUS)
 <661.3> Plastic Components and Systems Used to
Manufacturer Pharmaceutical Drug Product

Initial Assessment
 Initial assessment examines whether there are factors
present that would support the conclusion that the plastic
components and systems are fit for their intended use
without further characterization
• Demonstration of equivalence with a comparator
component or system would allow acceptance of the
component without further characterization
̶ Equivalence in purpose and composition of component or
system
̶ Equivalence in composition of DP(s)
̶ Equivalence in processing conditions
̶ Equivalence in product dosage form
 <661.3> Plastic Components and Systems Used to
Manufacturer Pharmaceutical Drug Product

Risk Dosage Forms Characterization of Plastic

Level Components or Systems
Risk Assessment A Low-risk dosage Baseline Assessment
forms, e.g., solid
 Determine the level of oral and liquid
oral, where the
Risk via a risk assessment liquid process
stream is part of
matrix. the
manufacturing

• Low (Level A) process for

either APIs or

• Moderate (Level B)
DPs

• High (Level C)
B Dosage forms Expanded Baseline Assessment
other than solid
oral and liquid
oral

C Dosage forms Full Assessment

other than solid
oral and liquid
oral
 <661.3> Plastic Components and Systems Used to
Manufacturer Pharmaceutical Drug Product

Testing
 Biological Reactivity
 Physicochemical Test
• Material and Component Extraction
̶ Extraction Conditions