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Achieving ''Zero'' Defects for Visible Particles in Injectables

Jennifer Johns, Paolo Golfetto, Tia Bush, et al.

PDA J Pharm Sci and Tech 2018, 72 640-650

Access the most recent version at doi:10.5731/pdajpst.2018.009027
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DISCLAIMER: The following paper is a special contribution from the Parenteral Drug Association (PDA). This article was
internally reviewed by PDA and the task force members and not peer-reviewed by the PDA Journal. Note: This PDA Paper
is protected by copyright and unauthorized distribution or use is prohibited..

PDA PAPERS

Achieving “Zero” Defects for Visible Particles in Injectables

JENNIFER JOHNS1, PAOLO GOLFETTO2, TIA BUSH3, GIANMAURIZIO FANTOZZI2, JOHN SHABUSHNIG4,*,
ANTHONY PERRY5, FRAN DEGRAZIO6, DOROTHEE STREICH7, JAHANVI MILLER8,
HERVE SOUKIASSIAN9, AMY STANTON10, and RICK WATSON11
1
Pfizer, Inc, N. Peapack, NJ, USA; 2Stevenato Group, Via Molinella, Padua, Italy; 3Amgen Inc., West Greenwich, RI,
USA; 4Insight Pharma Consulting, LLC, Marshall, MI, USA; 5Schott North America, Inc., Lebanon, PA, USA; 6West
Pharmaceutical Services, Inc., Exton, PA, USA; 7Bayer AG, Kaiser-Wilhelm-Allee, Leverkusen, Germany; 8Parenteral
Drug Association, Bethesda, MD, USA; 9Becton Dickinson, Le Pont-de-Claix, France; 10Amgen Inc., Thousand Oaks,
CA, USA; 11Merck & Co., West Point, PA, USA ©PDA, Inc. 2018

ABSTRACT: The reduction of visible particles in injectable products is an important element in the consistent
delivery of high-quality parenteral products. An important part of this effort is the control of particles that may
emanate from the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the
Pharmaceutical Manufacturers Forum (PMF), has undertaken the task of developing test methods to assess the
cleanliness of primary packaging components used in the manufacturing of sterile injectable products. Further
work is focused on end-to-end analysis of the supply chain to identify additional points where particles may enter
the finished product workflow. This includes shipment, receipt, transfer, and fill and finishing operations. This
information and appropriate corrective actions and control methods, coupled with appropriate patient risk-based
acceptance limits, are intended to provide better and more consistent supply of injectable products that meet
current compendial and good manufacturing practice (GMP) expectations. Aligning control limits between
supplier and pharmaceutical manufacturers will offer further improvement. This paper describes the formation
of a task force to address these needs and current progress to date.

KEYWORDS: Injectable products, Primary packaging components, Process improvement, Risk assessment, Visible
particles.

LAY ABSTRACT: Visible particles must be controlled in parenteral products. Such particles come from many sources
including the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the
Pharmaceutical Manufacturers Forum (PMF), has formed a task force to review and improve particle measurement
methods and perform an end-to-end analysis of how particles may enter into parenteral products. These activities are
intended to lead to more consistent control limits for visible particles and ultimately more consistent supply of high
quality injectable products.

1. Introduction propriate primary container selection, and the use of

controlled manufacturing conditions—followed by a
There has always been a demand for high-quality robust, visual inspection process. In recent years, there
injectable drugs. Because injectable drugs bypass the has been an increasing demand to reduce the residual
body’s normal defense mechanisms, great care must particle load in injectable drug products, resulting in an
be taken to control the risk of microbial, chemical, and increase in recalls associated with particles as can be
particle contamination. This can typically be accom- seen in Figure 1 (1). In some cases, these recalls have led
plished through careful formulation development, ap- to the shortage of critical drugs, putting patients at risk
(2). This is an industry-wide issue, and it is not
limited to any one company, global region, or drug
* Corresponding Author: e-mail: johnshabushnig@aol. product format.
com
The United States Pharmacopeia (USP), European
doi: 10.5731/pdajpst.2018.009027
Pharmacopoeia (EP), and the Japanese Pharmaco-

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limit for such particles difficult. These standards also

treat all visible particles equally, regardless of their
risk to the patient.

In early 2014, PDA assembled a team of physicians

and visual inspection experts to review and assess the
current clinical risks of visible particles in injectable
drug products. The resulting publication (6) provided
guidance on risk assessment to better align industry
Figure 1 actions with specific products and patient populations.
During this time, the USP was developing a general
Analysis of sterile drug product recalls 2010 –2017 chapter to better guide the selection of inspection
(1). conditions and acceptance criteria to ensure that “ev-
ery lot of all parenteral preparations is essentially free
from visible particulates” as stated in USP General
Chapter ⬍1⬎ Injections and Implanted Drug Products
poeia (JP)—although now closely aligned— have set
(Parenterals)—Product Quality Tests. This led to the
the requirement for finished products, which are in-
publication of USP General Chapter ⬍790⬎ Visible
tended for parenteral use (3–5), and they provide no
Particulates in Injections (3) which became an official
visible particle specifications for the materials that are
chapter on August 1, 2014.
used to produce these products. The USP and EP set
requirements that are to be used, along with 100%
While these actions have helped to reduce the number
inspection during the manufacturing process, to dem-
of recalls due to visible particles, as can be seen in
onstrate the process, have produced a batch that is
Figure 2 (1), further action is still needed. This figure
“essentially free” or “practically free” of visible par-
also highlights the results of the increasing concerns
ticulates. The JP follows this approach, but it states
by regulators and increasingly conservative actions
that, “Injections or vehicles must be clear and free taken by industry, rising to a peak in recall numbers in
from readily detectable foreign insoluble matters” (5). 2014. With the publication of USP General Chapter
A complete program for the control and monitoring of ⬍790⬎ in that year, both regulators and producers had
particulate matter in parenteral products remains an a better understanding of the inspection conditions and
essential prerequisite to meet global pharmacopoeial the quality levels expected for the finished product,
requirements. The standards state that the inspected which resulted in a drop in the number of recalls in the
units must be essentially free of visible particulates next few years. Much of the work done to date has
when examined without magnification (except for focused on the inspection requirements for filled and
optical correction as may be required to establish finished products. Further work is still required to
normal vision) against a black background and against improve the filling process and to address concerns
a white background. No quantitative size limit or upstream in the manufacturing process, including pri-
threshold has been established in the pharmacopoeias mary packaging materials. As with the filled and fin-
(3–5) to define what is visible. This lack of agreement ished drug product, it is important to have defined test
on the definition of visible as applied to particles, methods and clear requirements and specifications for
coupled with inspector variability and the probabilistic the components used to manufacture these products.
nature of visual inspection, can lead to uncertain This is needed for both the component producers to
outcomes. Continued advancement in automated in- develop reliable and appropriate processes as well as
spection technology and its deployment in the phar- end manufacturers to assess the quality of these com-
maceutical industry have helped to reduce the vari- ponents before use.
ability often associated with manual inspection
methods but do not fully address the uncertainty of Primary packaging components are not usually sub-
these measurements. Adding to the difficulty of jected to the 100% inspection that is required for the
establishing an appropriate standard is the lack of an finished and filled product, but these are often assessed
unambiguous measure of patient risk. The lack of by inspecting a sample of each batch. Particle detec-
controlled clinical studies assessing the impact of vis- tion can also be more difficult in these components
ible particles in human patients makes setting a safe because they cannot be put in motion as with particles

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Figure 2

Sterile drug product recalls due to particles by year, 2010 –2017 (1).

in a liquid product. Movement aids detection by both Manufacturers Forum (PMF). A cross-functional in-
the human eye (7) and automated inspection systems. dustry task force of industry experts was established
All of these are complicated by the probabilistic nature to lead this initiative. The project would look at the
of detecting particles in or on product or components. process from end-to-end, including suppliers of com-
Generally, the probability of detection in filled solu- ponents, as well as the pharmaceutical manufacturing
tions increases with increasing particle size and is processes, and focus on identifying potential sources
approximately 50% for a single 100 ␮m spherical of particles, accurate detection and measurement meth-
particle in a clear solution packaged in clear vials and ods for visible particles, and methods to mitigate the
approaches 100% for particles 200 ␮m in diameter (8). presence of visible particles in injectable drug prod-
The routine 100% inspection of filled products speci- ucts. The project was named Achieving “Zero” De-
fied by the Pharmacopeias (3–5) emphasizes detection fects for Visible Particles in Injectables. Zero was
and does not require identification or sizing. When an intentionally placed in quotes, recognizing that no
product or material is absolutely free of particles. The
analytical technique, such as that offered by recovery,
test and inspection methods used will ultimately de-
isolation, and microscopy is applied, an accurate mea-
termine what is visible or detectable. Appropriate
surement of particle size can be obtained and should
measurement methods and risk-based specifications
be assessed relative to the required visual inspection
are required to reliably deliver safe and effective prod-
detection performance. This leads to the need to set a
ucts to patients.
visible threshold for counting, similar to the subvisible
threshold of 10 ␮m and 25 ␮m currently in common
The task force will focus on visible particles in:
use (9).
● ready-to-fill (RTF), ready-to-use (RTU), and ready-
In September 2016, the PDA organized a meeting to-sterilize (RTS) materials and components (bulk
between suppliers of glass and elastomeric compo- components will be addressed in a later phase);
nents and pharmaceutical manufacturers to define a
viable pathway for a collaborative effort to further ● glass containers such as vials, syringes, and car-
reduce the number of recalls in the market. The tridges;
participants overwhelmingly voted to focus on
achieving zero defects for visible particles in inject- ● elastomer components such as stoppers, plungers,
ables. and syringe tip caps; and

To achieve this objective, a task force was established, ● secondary packaging associated with packaging
which was sponsored by PDA and the Pharmaceutical components such as bags.

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Bulk components are those that are subjected to fur- washing prior to use, and are not regulated by the
ther cleaning and sterilization processes by the phar- current standards with regard to visible particle load.
maceutical manufacturer in-house prior to use, while The assessment of bulk components will be considered
RTF, RTU, and RTS components are used without in a later phase.
further cleaning but are subjected to sterilization in the
case of RTS components. A significant part of this project will also include an
end-to-end assessment of where particles may be in-
The taskforce intends to establish a clearly defined troduced into finished filled product, either directly or
visible particle specification (e.g., size, type and quan- through contact with other component materials. This
tity) based on the potential risk of harm to patients. will use failure mode and effects analysis (FMEA)
While such specificity in a visible particle specifica- methodology to quantify particle sources with regard
tion is desirable, the lack of relevant clinical trials
to occurrence, detection, and severity. This analysis
owing to obvious ethical considerations limits the
will look upstream into the component manufacturing
ability to establish unequivocal safety limits as is
process and continue through the assembly of filled
typically done for other “impurities.” However, an
units. This model is intended to provide guidance for
initial review suggests that a visible threshold limit for
process improvement from lessons already learned.
particles between 100 and 150 ␮m and a separate limit
for fibers between 300 and 500 ␮m may be appropri-
ate. However, additional assessment work will be re- The task force will prepare a document summarizing
quired to establish practical limits. Such limits, while their findings and recommendations. Publication is
related to visual inspection capability, will be based on anticipated once method development and qualifica-
the performance of an alternate analytical method tion have been completed and associated risk assess-
(such as membrane filtration coupled with microscopic ments have been completed. A second phase is antic-
observation). These limits would be established and ipated to address bulk components that are processed
qualified through planned testing of the proposed mea- by the end user.
surement methods.
2. Project Structure
Thus far, a large body of anecdotal information has
been used to guide the understanding of clinical risk of Figure 3 provides an overview of the many process
visible particles. These are useful and provide guid- steps between raw materials, finished drug, and the
ance, but not an exact limit, for setting acceptance
patient.
criteria for injectable products and the primary pack-
aging used in their preparation. The lack of a specific
The first phase of the project, associated with RTF,
definition of what is a visible particle, coupled with
RTU, and RTS components, was further divided into
the normal variability of visual inspection processes,
four key steps:
has led to a wide range of practices and acceptance
limits applied to particles in injectable drug products
● Understanding the current criteria used to define
and their packaging materials.
patient risk, visible particle size and number and
The uncertainty associated with both clinical risk and their associated acceptance limits;
detection must be considered when undertaking a proj-
● process mapping with associated FMEA analysis;
ect of this nature, but it should not prevent the devel-
opment of practical guidance, which will be intended
● developing qualified methods with which to eval-
for use along with existing compendia and regulatory
and industry standards. uate components; and

● aligning and promoting these methods and accep-

Because of its broad scope, the project was broken into
two phases, and the first phase would limit the scope tance criteria within the industry.
to RTF, RTU, or RTS components. This was identified
as a critical gap in the process leading to filled prod- Figure 4 provides further detail regarding each of
uct, as these widely used primary packaging compo- these project steps in Phase 1 and a description of each
nents are often not evaluated or subjected to additional of these steps follows.

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Figure 3

End-to-end process view for sterile injectable drug product.

2.1. Understanding and Defining the Current State of by both suppliers and the pharmaceutical manufactur-
Visible Particle Measurement and Control for Primary ers to evaluate RTF, RTU, and RTS components.
Packaging Components and Establishing a Patient
Risk-Based Particle Size Threshold and Acceptance This involves examining two distinct but complemen-
Criteria tary paths for glass and rubber/elastomeric components.
Risk assessment methodologies and the commonality of
The focus of this part of the project is to establish a the process steps for both these components will be used
clear definition for what constitutes a “visible” particle as the starting point for self-evaluation and mitigation
and to develop standardized methods that can be used strategies. These in turn will result in the definition of

Figure 4

Phase 1: Achieving “zero” defects for visible particles in injectables.

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risk-based acceptance criteria for visible particles into the following categories: General, Medical Risk
for these components. Associated with Visible Particles, Regulatory and
Compendial Requirements, Test Methods and Accep-
2.2. Developing Qualified Methods With Which to tance Criteria for Primary Packaging Components, and
Evaluate Components Finished Product Inspection Methods and Acceptance
Criteria. The team considered undertaking a survey to
The work in this next step includes the review of gather additional information on current industry prac-
existing methods for detecting and quantifying visible tices, but it found sufficient information in the PDA
particles on or in the primary packaging materials surveys conducted in 2014 and 2015 to support this
described earlier. Included in the scope of this project work. A list of the key documents identified can be
is a review of current practices with the intent to found in Appendix 1.
qualify and harmonize these methods. This will be
done within the constraints of existing manufacturing The general findings were that no new relevant refer-
capabilities and best practice sharing without violating ences were identified and that no new test methods or
current antitrust regulations. acceptance criteria were found. Furthermore, no spe-
cific regulatory requirements or test methods for vis-
2.3. Aligning and Promoting the Acceptance Criteria ible particles in primary packaging components were
and Methods Within the Industry found. The existing test methods for primary packag-
ing favor collection followed by sizing and counting
On completion of the initial phase of work, the task of particles to assess suitability of a component or a
force will partner with existing standard-setting bodies batch. The general findings also indicate that there is
to institutionalize the best practices and limits identi- support for a lower limit to the visible range between
fied here. Established by consensus and supported by 100 and 150␮m in diameter from studies that assess
bodies equipped to develop industry standards, we will the probabilistic nature of human inspection perfor-
help drive our industry toward the desired goal of zero mance in filled and sealed containers (8). A reduced
visible particles in injectable products. detection ability for fibers may require a higher (or
larger-size threshold) for this type of particle.
The task force will then extend this approach, address-
ing issues and solutions in the areas of active pharma- Existing risk assessment tools and methods associated
ceutical ingredient (API) and drug product (DP) manu- with visible particles in injectable pharmaceutical
facturing and process equipment, as well as addressing products are currently being assessed. It is recognized
bulk packaging components in later project phases. that this is complicated by the wide variety of products
and the number of patients served, and care must be
3. Progress to Date taken to understand such risks. Such a tool should be
used to focus resources on the areas of the greatest risk
3.1. Literature Search and Risk Assessment rather than to diminish the need for rigorous current
GMP controls for particles in general.
A review of relevant literature associated with visible
particles in injectable pharmaceutical products was 3.2. Understanding Failure Modes, Probability of
undertaken to assess the current state of particle con- Occurrence, and Particle Detection
trol. It was important not to duplicate or create conflict
with existing guidance. This review included pub- Current industry particle control practices will be
lished benchmarking studies, regulatory and compen- benchmarked and patient risk-based acceptance crite-
dial guidance, and standards and test methods. Appli- ria will also be established. One focus is on under-
cation to both filled and sealed units, as well as standing the main particle generation mechanisms
primary packaging components, was included in the and/or entry routes within the entire production chain,
scope of this review. The search was based on previ- from suppliers (container and closure) to the final drug
ous searches, personal experience of the team mem- product (fill and finish). Based on industry surveys, the
bers, online Internet searches using Google, and key- five most common visible particle types (in order from
word search of the following databases: Books@Ovid, most common to the least common) that are identified
BIOSIS Previews, Embase, and Ovid MEDLINE. The in parenteral products are fibers, glass, product-
search yielded 43 relevant documents that were sorted related, rubber/elastomer, and metal (10).

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FMEA methodology will be used to identify the most can, from that information, establish an industry stan-
critical process areas and mechanisms that result in dard for what should be considered a “visible particle”
particle contamination for the five most common par- for analytical testing of primary packaging compo-
ticle types. Process steps will be generalized to be nents. More specifically, the report intends to establish
broadly applicable, but these will include specific best an industry-standard-size threshold for analytical test-
practices that can be applied in common manufactur- ing of particulate matter in primary packaging com-
ing settings. The team will leverage their experience ponents, and only particles above the size threshold
and industrial knowledge to contribute to this effort should be “counted” as visible particles. This size
with the goal of sharing best practices broadly and threshold could be used in both analytical testing
aligning on critical processes that can benefit from during component release by suppliers and can be used
additional focus and improvement with the goal of during incoming material acceptance testing by phar-
driving improvements across industry. maceutical manufacturing companies. Sampling from
various points in the supply chain will be useful for
Deliverables include: process optimization to better understand the contri-
bution of each operation and ultimately lead to better
● FMEA for manufacturing process (glass, elasto- control. The size threshold developed by the task force
mer, and fill and finish); and will not be intended to be applied to inspection of
filled drug product inspection and should not be ap-
● identification of most critical process steps within plied when the test method is simply inspection by the
manufacturing process for top five particles, focus- unaided human eye.
ing on RTF, RTU and RTS materials.
3.4. Glass Analytical Methods and Qualification
Thus far, significant observations include the critical- Strategy
ity of glass handling and limiting glass-to-glass
contact, robust environmental controls throughout the Completion of this work will result in a proposal for
process, careful transfer of materials between areas of an analytical method for the collection and quantifi-
different classification and cleanliness, and the impor- cation of visible particles in RTU glass containers.
tance of controlling the shedding and transfer of par-
ticles from secondary packaging. Today, there is no standardized industry method or
limit for visible particles that is used by both the glass
3.3. Develop Risk-Based Visible Particle-Size Threshold container suppliers and pharmaceutical manufactures,
and specifications are established between suppliers
The focus is the establishment of what should be and customers for each product supplied. This is fur-
considered a visible particle when performing analyt- ther complicated by the diversity of potential manu-
ical testing on primary packaging components. In drug facturing defects generated by both glass primary
products’ containers, extraneous matter is considered packaging suppliers and pharmaceutical manufactures.
“visible” when it is seen by the unaided human eye The sensitivity of any such method is affected by
under standard inspection conditions. For primary many variables including the size, shape, color, and
packaging components, there is a desire to set accep- reflectivity of the particle, as well as the specific
tance criteria for particles that ensure the drug product container size and shape.
requirements for visible particles are met; however,
there is no clear method or definition on what should The task force is developing an implementation strategy
be considered a visible particle if found on incoming for a visible particle assessment method for empty glass
component testing. Further adding to the challenge, it containers, which will include a qualification strategy,
is very typical for primary packaging component sup- which shows the effectiveness of the method, thus en-
pliers to perform particulate testing with analytical suring repeatable and accurate results industry wide.
methods that have the capability that goes far beyond
that of the unaided human eye. 3.5. Development of Analytical Methods and
Qualification Strategies for Stoppers and Bags
The report produced by the task force will include an
assessment of existing technical literature on the sci- The goal is to align the stopper analytical methodol-
ence of particle detection in drug products, and they ogy used for the detection of visible particles released

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from processed components (RTF, RTS, and RTU) opportunities to reduce particle entry throughout the
and from their final packaging. Currently, there is no supply chain. With this alignment, quantification and
standard analytical methodology that is used by both ultimately reduction and improved control are possi-
stopper supplier and the pharmaceutical manufactur- bly moving us toward meeting the goal of zero parti-
ing customer. There is no requirement to test stoppers cles in injections.
from final packaging, which causes disconnect be-
tween what is tested by suppliers and what is received The completion of this first phase is planned for 2018
by customers. Additionally, there are no standardized and planning for the second phase has already begun.
specifications for visible particles on RTF, RTS, and This initiative welcomes new task force members who
RTU stoppers, rather specifications are agreed upon can contribute to this project in the current or subse-
between customer and supplier for each product. quent phases.

Furthermore, the goal of aligning the suppliers and Acknowledgments

customers on an analytical method used for visible
particles will be achieved through the implementation The authors wish to thank Martin Van Trieste and the
of a method qualification strategy. The method quali- leadership of the Pharmaceutical Manufacturers Fo-
fication will serve to demonstrate the ability of the rum (PMF) for their foresight and support of this
analytical method to be used by the entire industry to project. The authors would also like to acknowledge
generate accurate and repeatable results for visible and thank the members of the project team, from
particles greater than the identified and agreed-upon both component suppliers and pharmaceutical man-
size threshold. ufacturers, who have contributed to the work pre-
sented herein.
FMEA will also be applied to production and use of
elastomer components. A study comparing the meth- Conflict of Interest Declaration
ods used by each of the stopper suppliers will be
performed to determine gaps and identify best prac- The authors declare no conflict of interest related to
tices. Work by this subteam will include development the development of this manuscript (i.e., no competing
and qualification of an appropriate test method for interests). The authors acknowledge that they have no
visible particles released from elastomer components. involvement in any organization or entity with any
A qualification strategy has been agreed upon and a financial or nonfinancial interest in the subject matter
qualification protocol is in the process of being devel- or materials discussed in this manuscript.
oped for use in this study.
References
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