10.5731/pdajpst.2018.009027Access the most recent version at doi: 640-65072, 2018 PDA J Pharm Sci and Tech

 Jennifer Johns, Paolo Golfetto, Tia Bush, et al. Achieving ''Zero'' Defects for Visible Particles in Injectables  

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PDA PAPERS

Achieving “Zero” Defects for Visible Particles in InjectablesJENNIFER JOHNS1, PAOLO GOLFETTO2, TIA BUSH3, GIANMAURIZIO FANTOZZI2, JOHN SHABUSHNIG4,*,ANTHONY PERRY5, FRAN DEGRAZIO6, DOROTHEE STREICH7, JAHANVI MILLER8,HERVE SOUKIASSIAN9, AMY STANTON10, and RICK WATSON11

1Pfizer, 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; 6WestPharmaceutical Services, Inc., Exton, PA, USA; 7Bayer AG, Kaiser-Wilhelm-Allee, Leverkusen, Germany; 8ParenteralDrug 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 consistentdelivery of high-quality parenteral products. An important part of this effort is the control of particles that mayemanate from the primary packaging materials. The Parenteral Drug Association (PDA), with the support of thePharmaceutical Manufacturers Forum (PMF), has undertaken the task of developing test methods to assess thecleanliness of primary packaging components used in the manufacturing of sterile injectable products. Furtherwork is focused on end-to-end analysis of the supply chain to identify additional points where particles may enterthe finished product workflow. This includes shipment, receipt, transfer, and fill and finishing operations. Thisinformation and appropriate corrective actions and control methods, coupled with appropriate patient risk-basedacceptance limits, are intended to provide better and more consistent supply of injectable products that meetcurrent compendial and good manufacturing practice (GMP) expectations. Aligning control limits betweensupplier and pharmaceutical manufacturers will offer further improvement. This paper describes the formationof a task force to address these needs and current progress to date.

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

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

1. Introduction

There has always been a demand for high-qualityinjectable drugs. Because injectable drugs bypass thebody’s normal defense mechanisms, great care mustbe taken to control the risk of microbial, chemical, andparticle contamination. This can typically be accom-plished through careful formulation development, ap-

propriate primary container selection, and the use ofcontrolled manufacturing conditions—followed by arobust, visual inspection process. In recent years, therehas been an increasing demand to reduce the residualparticle load in injectable drug products, resulting in anincrease in recalls associated with particles as can beseen in Figure 1 (1). In some cases, these recalls have ledto the shortage of critical drugs, putting patients at risk(2). This is an industry-wide issue, and it is notlimited to any one company, global region, or drugproduct format.

The United States Pharmacopeia (USP), EuropeanPharmacopoeia (EP), and the Japanese Pharmaco-

* Corresponding Author: e-mail: johnshabushnig@aol.com

doi: 10.5731/pdajpst.2018.009027

DISCLAIMER: The following paper is a special contribution from the Parenteral Drug Association (PDA). This article wasinternally reviewed by PDA and the task force members and not peer-reviewed by the PDA Journal. Note: This PDA Paperis protected by copyright and unauthorized distribution or use is prohibited..

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poeia (JP)—although now closely aligned— have setthe requirement for finished products, which are in-tended for parenteral use (3–5), and they provide novisible particle specifications for the materials that areused to produce these products. The USP and EP setrequirements that are to be used, along with 100%inspection during the manufacturing process, to dem-onstrate the process, have produced a batch that is“essentially free” or “practically free” of visible par-ticulates. The JP follows this approach, but it statesthat, “Injections or vehicles must be clear and freefrom readily detectable foreign insoluble matters” (5).A complete program for the control and monitoring ofparticulate matter in parenteral products remains anessential prerequisite to meet global pharmacopoeialrequirements. The standards state that the inspectedunits must be essentially free of visible particulateswhen examined without magnification (except foroptical correction as may be required to establishnormal vision) against a black background and againsta white background. No quantitative size limit orthreshold has been established in the pharmacopoeias(3–5) to define what is visible. This lack of agreementon the definition of visible as applied to particles,coupled with inspector variability and the probabilisticnature of visual inspection, can lead to uncertainoutcomes. Continued advancement in automated in-spection technology and its deployment in the phar-maceutical industry have helped to reduce the vari-ability often associated with manual inspectionmethods but do not fully address the uncertainty ofthese measurements. Adding to the difficulty ofestablishing an appropriate standard is the lack of anunambiguous measure of patient risk. The lack ofcontrolled clinical studies assessing the impact of vis-ible particles in human patients makes setting a safe

limit for such particles difficult. These standards alsotreat all visible particles equally, regardless of theirrisk to the patient.

In early 2014, PDA assembled a team of physiciansand visual inspection experts to review and assess thecurrent clinical risks of visible particles in injectabledrug products. The resulting publication (6) providedguidance on risk assessment to better align industryactions with specific products and patient populations.During this time, the USP was developing a generalchapter to better guide the selection of inspectionconditions and acceptance criteria to ensure that “ev-ery lot of all parenteral preparations is essentially freefrom visible particulates” as stated in USP GeneralChapter �1� Injections and Implanted Drug Products(Parenterals)—Product Quality Tests. This led to thepublication of USP General Chapter �790� VisibleParticulates in Injections (3) which became an officialchapter on August 1, 2014.

While these actions have helped to reduce the numberof recalls due to visible particles, as can be seen inFigure 2 (1), further action is still needed. This figurealso highlights the results of the increasing concernsby regulators and increasingly conservative actionstaken by industry, rising to a peak in recall numbers in2014. With the publication of USP General Chapter�790� in that year, both regulators and producers hada better understanding of the inspection conditions andthe quality levels expected for the finished product,which resulted in a drop in the number of recalls in thenext few years. Much of the work done to date hasfocused on the inspection requirements for filled andfinished products. Further work is still required toimprove the filling process and to address concernsupstream in the manufacturing process, including pri-mary packaging materials. As with the filled and fin-ished drug product, it is important to have defined testmethods and clear requirements and specifications forthe components used to manufacture these products.This is needed for both the component producers todevelop reliable and appropriate processes as well asend manufacturers to assess the quality of these com-ponents before use.

Primary packaging components are not usually sub-jected to the 100% inspection that is required for thefinished and filled product, but these are often assessedby inspecting a sample of each batch. Particle detec-tion can also be more difficult in these componentsbecause they cannot be put in motion as with particles

Figure 1

Analysis of sterile drug product recalls 2010 –2017(1).

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in a liquid product. Movement aids detection by boththe human eye (7) and automated inspection systems.All of these are complicated by the probabilistic natureof detecting particles in or on product or components.Generally, the probability of detection in filled solu-tions increases with increasing particle size and isapproximately 50% for a single 100 �m sphericalparticle in a clear solution packaged in clear vials andapproaches 100% for particles 200 �m in diameter (8).The routine 100% inspection of filled products speci-fied by the Pharmacopeias (3–5) emphasizes detectionand does not require identification or sizing. When ananalytical technique, such as that offered by recovery,isolation, and microscopy is applied, an accurate mea-surement of particle size can be obtained and shouldbe assessed relative to the required visual inspectiondetection performance. This leads to the need to set avisible threshold for counting, similar to the subvisiblethreshold of 10 �m and 25 �m currently in commonuse (9).

In September 2016, the PDA organized a meetingbetween suppliers of glass and elastomeric compo-nents and pharmaceutical manufacturers to define aviable pathway for a collaborative effort to furtherreduce the number of recalls in the market. Theparticipants overwhelmingly voted to focus onachieving zero defects for visible particles in inject-ables.

To achieve this objective, a task force was established,which was sponsored by PDA and the Pharmaceutical

Manufacturers Forum (PMF). A cross-functional in-dustry task force of industry experts was establishedto lead this initiative. The project would look at theprocess from end-to-end, including suppliers of com-ponents, as well as the pharmaceutical manufacturingprocesses, and focus on identifying potential sourcesof particles, accurate detection and measurement meth-ods for visible particles, and methods to mitigate thepresence of visible particles in injectable drug prod-ucts. The project was named Achieving “Zero” De-fects for Visible Particles in Injectables. Zero wasintentionally placed in quotes, recognizing that noproduct or material is absolutely free of particles. Thetest and inspection methods used will ultimately de-termine what is visible or detectable. Appropriatemeasurement methods and risk-based specificationsare required to reliably deliver safe and effective prod-ucts to patients.

The task force will focus on visible particles in:

● ready-to-fill (RTF), ready-to-use (RTU), and ready-to-sterilize (RTS) materials and components (bulkcomponents will be addressed in a later phase);

● glass containers such as vials, syringes, and car-tridges;

● elastomer components such as stoppers, plungers,and syringe tip caps; and

● secondary packaging associated with packagingcomponents such as bags.

Figure 2

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

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Bulk components are those that are subjected to fur-ther cleaning and sterilization processes by the phar-maceutical manufacturer in-house prior to use, whileRTF, RTU, and RTS components are used withoutfurther cleaning but are subjected to sterilization in thecase of RTS components.

The taskforce intends to establish a clearly definedvisible particle specification (e.g., size, type and quan-tity) based on the potential risk of harm to patients.While such specificity in a visible particle specifica-tion is desirable, the lack of relevant clinical trialsowing to obvious ethical considerations limits theability to establish unequivocal safety limits as istypically done for other “impurities.” However, aninitial review suggests that a visible threshold limit forparticles between 100 and 150 �m and a separate limitfor fibers between 300 and 500 �m may be appropri-ate. However, additional assessment work will be re-quired to establish practical limits. Such limits, whilerelated to visual inspection capability, will be based onthe performance of an alternate analytical method(such as membrane filtration coupled with microscopicobservation). These limits would be established andqualified through planned testing of the proposed mea-surement methods.

Thus far, a large body of anecdotal information hasbeen used to guide the understanding of clinical risk ofvisible particles. These are useful and provide guid-ance, but not an exact limit, for setting acceptancecriteria for injectable products and the primary pack-aging used in their preparation. The lack of a specificdefinition of what is a visible particle, coupled withthe normal variability of visual inspection processes,has led to a wide range of practices and acceptancelimits applied to particles in injectable drug productsand their packaging materials.

The uncertainty associated with both clinical risk anddetection must be considered when undertaking a proj-ect of this nature, but it should not prevent the devel-opment of practical guidance, which will be intendedfor use along with existing compendia and regulatoryand industry standards.

Because of its broad scope, the project was broken intotwo phases, and the first phase would limit the scopeto RTF, RTU, or RTS components. This was identifiedas a critical gap in the process leading to filled prod-uct, as these widely used primary packaging compo-nents are often not evaluated or subjected to additional

washing prior to use, and are not regulated by thecurrent standards with regard to visible particle load.The assessment of bulk components will be consideredin a later phase.

A significant part of this project will also include anend-to-end assessment of where particles may be in-troduced into finished filled product, either directly orthrough contact with other component materials. Thiswill use failure mode and effects analysis (FMEA)methodology to quantify particle sources with regardto occurrence, detection, and severity. This analysiswill look upstream into the component manufacturingprocess and continue through the assembly of filledunits. This model is intended to provide guidance forprocess improvement from lessons already learned.

The task force will prepare a document summarizingtheir findings and recommendations. Publication isanticipated once method development and qualifica-tion have been completed and associated risk assess-ments have been completed. A second phase is antic-ipated to address bulk components that are processedby the end user.

2. Project Structure

Figure 3 provides an overview of the many processsteps between raw materials, finished drug, and thepatient.

The first phase of the project, associated with RTF,RTU, and RTS components, was further divided intofour key steps:

● Understanding the current criteria used to definepatient risk, visible particle size and number andtheir associated acceptance limits;

● process mapping with associated FMEA analysis;

● developing qualified methods with which to eval-uate components; and

● aligning and promoting these methods and accep-tance criteria within the industry.

Figure 4 provides further detail regarding each ofthese project steps in Phase 1 and a description of eachof these steps follows.

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2.1. Understanding and Defining the Current State ofVisible Particle Measurement and Control for PrimaryPackaging Components and Establishing a PatientRisk-Based Particle Size Threshold and AcceptanceCriteria

The focus of this part of the project is to establish aclear definition for what constitutes a “visible” particleand to develop standardized methods that can be used

by both suppliers and the pharmaceutical manufactur-ers to evaluate RTF, RTU, and RTS components.

This involves examining two distinct but complemen-tary paths for glass and rubber/elastomeric components.Risk assessment methodologies and the commonality ofthe process steps for both these components will be usedas the starting point for self-evaluation and mitigationstrategies. These in turn will result in the definition of

Figure 3

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

Figure 4

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

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risk-based acceptance criteria for visible particlesfor these components.

2.2. Developing Qualified Methods With Which toEvaluate Components

The work in this next step includes the review ofexisting methods for detecting and quantifying visibleparticles on or in the primary packaging materialsdescribed earlier. Included in the scope of this projectis a review of current practices with the intent toqualify and harmonize these methods. This will bedone within the constraints of existing manufacturingcapabilities and best practice sharing without violatingcurrent antitrust regulations.

2.3. Aligning and Promoting the Acceptance Criteriaand Methods Within the Industry

On completion of the initial phase of work, the taskforce will partner with existing standard-setting bodiesto institutionalize the best practices and limits identi-fied here. Established by consensus and supported bybodies equipped to develop industry standards, we willhelp drive our industry toward the desired goal of zerovisible particles in injectable products.

The task force will then extend this approach, address-ing issues and solutions in the areas of active pharma-ceutical ingredient (API) and drug product (DP) manu-facturing and process equipment, as well as addressingbulk packaging components in later project phases.

3. Progress to Date

3.1. Literature Search and Risk Assessment

A review of relevant literature associated with visibleparticles in injectable pharmaceutical products wasundertaken to assess the current state of particle con-trol. It was important not to duplicate or create conflictwith existing guidance. This review included pub-lished benchmarking studies, regulatory and compen-dial guidance, and standards and test methods. Appli-cation to both filled and sealed units, as well asprimary packaging components, was included in thescope of this review. The search was based on previ-ous searches, personal experience of the team mem-bers, online Internet searches using Google, and key-word search of the following databases: Books@Ovid,BIOSIS Previews, Embase, and Ovid MEDLINE. Thesearch yielded 43 relevant documents that were sorted

into the following categories: General, Medical RiskAssociated with Visible Particles, Regulatory andCompendial Requirements, Test Methods and Accep-tance Criteria for Primary Packaging Components, andFinished Product Inspection Methods and AcceptanceCriteria. The team considered undertaking a survey togather additional information on current industry prac-tices, but it found sufficient information in the PDAsurveys conducted in 2014 and 2015 to support thiswork. A list of the key documents identified can befound in Appendix 1.

The general findings were that no new relevant refer-ences were identified and that no new test methods oracceptance criteria were found. Furthermore, no spe-cific regulatory requirements or test methods for vis-ible particles in primary packaging components werefound. The existing test methods for primary packag-ing favor collection followed by sizing and countingof particles to assess suitability of a component or abatch. The general findings also indicate that there issupport for a lower limit to the visible range between100 and 150�m in diameter from studies that assessthe probabilistic nature of human inspection perfor-mance in filled and sealed containers (8). A reduceddetection ability for fibers may require a higher (orlarger-size threshold) for this type of particle.

Existing risk assessment tools and methods associatedwith visible particles in injectable pharmaceuticalproducts are currently being assessed. It is recognizedthat this is complicated by the wide variety of productsand the number of patients served, and care must betaken to understand such risks. Such a tool should beused to focus resources on the areas of the greatest riskrather than to diminish the need for rigorous currentGMP controls for particles in general.

3.2. Understanding Failure Modes, Probability ofOccurrence, and Particle Detection

Current industry particle control practices will bebenchmarked and patient risk-based acceptance crite-ria will also be established. One focus is on under-standing the main particle generation mechanismsand/or entry routes within the entire production chain,from suppliers (container and closure) to the final drugproduct (fill and finish). Based on industry surveys, thefive most common visible particle types (in order frommost common to the least common) that are identifiedin parenteral products are fibers, glass, product-related, rubber/elastomer, and metal (10).

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FMEA methodology will be used to identify the mostcritical process areas and mechanisms that result inparticle contamination for the five most common par-ticle types. Process steps will be generalized to bebroadly applicable, but these will include specific bestpractices that can be applied in common manufactur-ing settings. The team will leverage their experienceand industrial knowledge to contribute to this effortwith the goal of sharing best practices broadly andaligning on critical processes that can benefit fromadditional focus and improvement with the goal ofdriving improvements across industry.

Deliverables include:

● FMEA for manufacturing process (glass, elasto-mer, and fill and finish); and

● identification of most critical process steps withinmanufacturing process for top five particles, focus-ing on RTF, RTU and RTS materials.

Thus far, significant observations include the critical-ity of glass handling and limiting glass-to-glasscontact, robust environmental controls throughout theprocess, careful transfer of materials between areas ofdifferent classification and cleanliness, and the impor-tance of controlling the shedding and transfer of par-ticles from secondary packaging.

3.3. Develop Risk-Based Visible Particle-Size Threshold

The focus is the establishment of what should beconsidered a visible particle when performing analyt-ical testing on primary packaging components. In drugproducts’ containers, extraneous matter is considered“visible” when it is seen by the unaided human eyeunder standard inspection conditions. For primarypackaging components, there is a desire to set accep-tance criteria for particles that ensure the drug productrequirements for visible particles are met; however,there is no clear method or definition on what shouldbe considered a visible particle if found on incomingcomponent testing. Further adding to the challenge, itis very typical for primary packaging component sup-pliers to perform particulate testing with analyticalmethods that have the capability that goes far beyondthat of the unaided human eye.

The report produced by the task force will include anassessment of existing technical literature on the sci-ence of particle detection in drug products, and they

can, from that information, establish an industry stan-dard for what should be considered a “visible particle”for analytical testing of primary packaging compo-nents. More specifically, the report intends to establishan industry-standard-size threshold for analytical test-ing of particulate matter in primary packaging com-ponents, and only particles above the size thresholdshould be “counted” as visible particles. This sizethreshold could be used in both analytical testingduring component release by suppliers and can be usedduring incoming material acceptance testing by phar-maceutical manufacturing companies. Sampling fromvarious points in the supply chain will be useful forprocess optimization to better understand the contri-bution of each operation and ultimately lead to bettercontrol. The size threshold developed by the task forcewill not be intended to be applied to inspection offilled drug product inspection and should not be ap-plied when the test method is simply inspection by theunaided human eye.

3.4. Glass Analytical Methods and QualificationStrategy

Completion of this work will result in a proposal foran analytical method for the collection and quantifi-cation of visible particles in RTU glass containers.

Today, there is no standardized industry method orlimit for visible particles that is used by both the glasscontainer suppliers and pharmaceutical manufactures,and specifications are established between suppliersand customers for each product supplied. This is fur-ther complicated by the diversity of potential manu-facturing defects generated by both glass primarypackaging suppliers and pharmaceutical manufactures.The sensitivity of any such method is affected bymany variables including the size, shape, color, andreflectivity of the particle, as well as the specificcontainer size and shape.

The task force is developing an implementation strategyfor a visible particle assessment method for empty glasscontainers, which will include a qualification strategy,which shows the effectiveness of the method, thus en-suring repeatable and accurate results industry wide.

3.5. Development of Analytical Methods andQualification Strategies for Stoppers and Bags

The goal is to align the stopper analytical methodol-ogy used for the detection of visible particles released

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from processed components (RTF, RTS, and RTU)and from their final packaging. Currently, there is nostandard analytical methodology that is used by bothstopper supplier and the pharmaceutical manufactur-ing customer. There is no requirement to test stoppersfrom final packaging, which causes disconnect be-tween what is tested by suppliers and what is receivedby customers. Additionally, there are no standardizedspecifications for visible particles on RTF, RTS, andRTU stoppers, rather specifications are agreed uponbetween customer and supplier for each product.

Furthermore, the goal of aligning the suppliers andcustomers on an analytical method used for visibleparticles will be achieved through the implementationof a method qualification strategy. The method quali-fication will serve to demonstrate the ability of theanalytical method to be used by the entire industry togenerate accurate and repeatable results for visibleparticles greater than the identified and agreed-uponsize threshold.

FMEA will also be applied to production and use ofelastomer components. A study comparing the meth-ods used by each of the stopper suppliers will beperformed to determine gaps and identify best prac-tices. Work by this subteam will include developmentand qualification of an appropriate test method forvisible particles released from elastomer components.A qualification strategy has been agreed upon and aqualification protocol is in the process of being devel-oped for use in this study.

Work in this subteam extends to the bags used topackage elastomer components, as these can be asignificant source of particles. Gaps in the currenttesting methodology have been identified, and a guid-ance for particle testing in bags has been completed.The methodology to be applied to bags will follow thesame development and qualification strategy as thatfor the elastomeric components themselves.

4. Conclusions

Upon completion of the work of this cross-functionalteam, a common definition of what is a visible particle(size and type) and how to evaluate if visible particlesare present (quantitative methods) will be available foruse by both component suppliers and pharmaceuticalmanufacturers. These will permit a common approachto process evaluation and mitigation strategies. Pro-cess mapping and risk analysis will further identify

opportunities to reduce particle entry throughout thesupply chain. With this alignment, quantification andultimately reduction and improved control are possi-bly moving us toward meeting the goal of zero parti-cles in injections.

The completion of this first phase is planned for 2018and planning for the second phase has already begun.This initiative welcomes new task force members whocan contribute to this project in the current or subse-quent phases.

Acknowledgments

The authors wish to thank Martin Van Trieste and theleadership of the Pharmaceutical Manufacturers Fo-rum (PMF) for their foresight and support of thisproject. The authors would also like to acknowledgeand thank the members of the project team, fromboth component suppliers and pharmaceutical man-ufacturers, who have contributed to the work pre-sented herein.

Conflict of Interest Declaration

The authors declare no conflict of interest related tothe development of this manuscript (i.e., no competinginterests). The authors acknowledge that they have noinvolvement in any organization or entity with anyfinancial or nonfinancial interest in the subject matteror materials discussed in this manuscript.

References

1. Shabushnig, J. Archive for Recalls, Market With-drawals & Safety Alerts. Food Drug Administra-tion, available from www.fda.gov/Safety/Recalls/ArchiveRecalls/default.htm (accessed February 10,2018).

2. Current Drug Shortages, American Society ofHospital Pharmacists (ASHP), available fromwww.ashp.org/drug-shortages/current-shortages(accessed January 27, 2018).

3. General Chapter �790� Visible Particulates inInjections, United States Pharmacopeia (USP)USP 40/NF 35, available from https://www.uspnf.com/ (accessed September 26, 2018).

4. Chapter 2.9.20 Particulate Contamination: VisibleParticles, European Pharmacopeia (EP), Eudralex,

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Ph. Eur. 8th Ed., available from http://pharmeuropa.edqm.eu/home/ (accessed on October 14, 2018).

5. Chapter 6.06 Foreign Insoluble Matter Test for In-jections, The Japanese Pharmacopeia (JP) 16th Ed,English translation, available from http://jpdb.nihs.go.jp/jp16e/ (accessed on October 14, 2018).

6. Bukofzer, S.; Ayres, J.; Chavez, A.; Devera; M.,Miller, J.; Ross, D.; Shabushnig, J.; Vargo, S.;Watson, H.; Watson, R.; Industry Perspective onthe Medical Risk of Visible Particles in InjectableDrug Products. PDA J. Pharm. Sci. Technol.2015, 69 (1), 123–139.

7. Petersen, H. E.; Dugas, D. The Relative Impor-tance of Contrast and Motion in Visual Target

Detection., The Rand Corporation, Availablefrom www.rand.org/pubs/reports/R0688.html,Report R-688-PR, 1971.

8. Shabushnig, J.; Melchore, J.; Geiger, M.; Chrai,S.; Gerger, M. A Proposed Working Standard forValidation of Particulate Inspection in Sterile So-lutions, Paper presented at the PDA Annual Meet-ing, Philadelphia, PA, November 2– 4, 1995.

9. General Chapter �788� Particulate Matter in In-jections, United States Pharmacopeia (USP) USP40/NF 35, www.usp.org, 2018 (Chapter harmo-nized with EP 2.20.19 and JP 6.07).

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APPENDIX Literature Search Document List.

1. General

Parenteral Drug Association. PDA Survey: 2014 Vi-sual Inspection. PDA: Bethesda, Md., 2015.

Parenteral Drug Association. PDA Survey: 2015 Par-ticulate Matter in Difficult to Inspect Parenterals.PDA: Bethesda, Md., 2016.

Langille, S. E. Particulate Matter in Injectable DrugProducts. PDA J. Pharm. Sci. Technol. 2013, 67 (3),186 –200.

Davis, K., et al. Recommendations for Testing, Eval-uation, and Control of Particulates from Single-UseProcess Equipment; Bio-Process Systems Alliance(BPSA): Washington, DC, 2014.

ECA Visual Inspection Group. Good Practice Paper:Visual Inspection of Medicinal Products for Paren-teral Use; ECA Foundation: Heidelberg, 2014.

Borchert, S., et al. Particulate Matter in ParenteralProducts: A Review. PDA J. Pharm. Sci. Technol.1986, 40 (5), 212–237.

Kim, J., Schildt, D., et al. Investigation of Foreign-Particle Contamination: Practical Application of FT-IR, Raman, and SEM-EDS Technologies. BioProcessInternational 2016, 14 (8).

Mathonet, S., et al. A Biopharmaceutical IndustryPerspective on the Control of Visible Particles inBiotechnology-Derived Injectable Drug Products.PDA J. Pharm. Sci. Technol. 2016, 70 (4), 392– 408.

Shabushnig, J., et al. A Proposed Working Standardfor Validation of Particulate Inspection in Sterile So-lutions. Presented at PDA Annual Meeting, Philadel-phia, Pa., 1995.

Aldrich, S., Cherris, R., Shabushnig, J. Visual Inspec-tion and Particulate Control. DHI Publishing: Scotts-dale, Ar., 2016. www.pda.org/bookstore.

2. Medical Risk Associated with Visible Particles

Garvin, J. M., Gunner, B. W. The Harmful Effects ofParticles in Intravenous Fluids. Med. J. Australia1964, 2, 1– 6.

Garvin, J. M., Gunner, B. W. Intravenous Fluids: ASolution Containing such Particles Must Not be Used.Med. J. Australia 1964, 2, 140 –145.

Turco, S., Davis, N. Glass Particles in IntravenousInjections. New Engl. J. Med. 1972, 287 (3), 1204 –1205.

Thomas, W., Lee, Y. Particles in Intravenous Solu-tions: A Review. New Zeal. Med. J. 1974, 80, 170 –178.

Bukofzer, S., et al. Industry Perspective on the Med-ical Risk of Visible Particles in Injectable Drug Prod-ucts. PDA J. Pharm. Sci. Technol. 2015, 69 (1), 123–139.

3. Regulatory Requirements

Note: requirements found in pharmacopeias are listedin sections 4 and 5.

U.S. Food and Drug Administration. Federal Food,Drug and Cosmetic Act, Chapter V: Drugs and De-vices, Section 510; U.S. Government Printing Office:Washington, DC, 2006.

U.S. Food and Drug Administration. 21 CFR Part 211,Current Good Manufacturing Practice for FinishedPharmaceuticals; U.S. Government Printing Office:Washington, DC, 1978. www.ecfr.gov.

4. Test Methods and Acceptance Criteria forPrimary Packaging Components

International Standards Organization. ISO 8871-3Elastomeric Parts for Parenterals and for Devices forPharmaceutical Use—Part 3: Determination of re-leased-particle count. ISO: Geneva, 2003.

Institute of Environmental Sciences and Technology.IEST-STD-CC1246E: Product Cleanliness Levels—Applications, Requirements, and Determination; IEST:Schaumburg, Ill., 2013.

Parenteral Drug Association. Technical Report No. 43,Revised 2013, Identification and Classification of Non-conformities in Molded and Tubular Glass Containersfor Pharmaceutical Manufacturing Covering Ampules,Bottles, Cartridges, Syringes and Vials; PDA:Bethesda, Md., 2013.

Parenteral Drug Association. Technical Report No.76: Identification and Classification of Visible Non-

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conformities in Elastomeric Components and Alumi-num Seals for Parenteral Packaging; PDA: Bethesda,Md., 2016.

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5. Finished Product Inspection Methods andAcceptance Criteria

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650 PDA Journal of Pharmaceutical Science and Technology

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