USP Reference Standards 11 USP Particle Count RS . However, it may be necessary to test some preparations Testing would be performed by trained and qualified human operators. visible particles by one or both of these methods. Fresenius Kabi Canada Ltd. has identified visible particulate matter in certain vials of Sodium Acetate Injection, USP from lot 6126554 during routine retention sample testing. The USP has suggested different particle categories: . To ensure this, the USP <788> Particulate Matter in Injections test is employed for measuring the size and count of sub-visible particles in parenteral drugs, as shown in Figure 1. 1:00 p.m. In this event, a quantitative dilu-volume of less than 100 mL, apply the criteria of Test 2.B. The particulate matter (between 1 m and 30 mm) of infused therapies used in ICUs for patients suffering from either septic shock or acute respiratory distress syndrome was measured in vitro over 6 h using a dynamic image analysis device, so that both overall particulate contamination and particle sizes could be determined. Stage 1: uses light obscuration . In the most of injectables, Light Obscuration Method is preferred. this guidance addresses the development and implementation of a holistic, risk-based approach to visible particulate control that incorporates product development, manufacturing controls, visual. LO detects particles based on blockage of light by individual particles passing through a light sensing zone and provides particle size and counts, assuming spherical shape of particles. The concerned seemed to begin when USP created chapter <1> titled "injections"it was stated that each batch of drug products had to be "essentially free" of visible particles. Lunch. The USP <788> Particulate Matter in Injections general chapter is used to determine the count and size of undissolved particles in injection solutions 10 and 25 m. USP 35Physical Tests / 788 Particulate Matter in Injections341 brane filter, and two suitable illuminators to provide tory steps must be repeated until the environment, glass- episcopic illumination in addition to oblique illumination. Improving Flow Imaging Microscopy Particle Class ification through Deep . recommends that the official pharmacopoeial texts, Ph.Eur. According to USP compendial methods and studies of visual inspection processes, particulate contamination in parenteral drug products falls into two size classifications: subvisible for particles <100 m in size (USP <788>), and visible for those >100 m in size (USP <790>). to be "essentially free" of visible particles and USP <789> strictly limits subvisible particles in ophthalmic solutions. visible and subvisible. It was never clear of what an "acceptable level" for particulate matter was. matter is the first step in characterizing particulate . are national USP text, and therefore not part of the harmo- . "Every container in which the contents show evidence of visible particulates must be rejected". USP 788 describes two methods for analyzing particulates in injections and parenteral infusions: light obscuration (method 1) and microscopic (method 2). Identify particulate matter when performing Investigations Must use statistically sound sampling plan for AQL inspection. If needed, add stepwise In this case, visible means that particles can be detected with high . It is important for pharmacists to conduct particulate matter testing on parenteral solutions, as particulate matter in large numbers can cause harm to patients. and USP distinguish between visible and subvisible particles. In the pharmaceutical industry, particulate matter is an obligatory critical quality attribute (CQA) for parenterally administered medicines, i.e. Visible particulate is loosely defined as any particulate that can be detected with the unaided eye. Regulations direct drug product manufacturer s to exclude foreign matter and minimize foreign particle content. The standards for measuring SbVP particles in parenteral products are USP <788>, 17 EP 2.9.19, 18 and JP 6.07. We will use the term biopharmaceuticals to refer to products covered under USP<1045>. The guidance also clarifies that 20 meeting an applicable United States Pharmacopeia (USP) 3 compendial standard alone is not. However, USP <789> is subject to interpretation. Visible particles are detectable by eye under defined conditions, hence typically . Dounce, Susan M. PhD *; Laskina, . . Testing per USP methods assures compounding personnel that their products meet the requirements for sub-visible particles. USP <1> Injections and Implanted Drug Products (Parenteral): "Each final container of all parenteral preparations should be inspected to the extent possible for the presence of observable foreign and particulate matter in its contents". LO is the preferred method and the microscopy particle count test should be applied when LO is not suitable, that is, drug . PARTICULATE MATTER FROM SYRINGES USED FOR INTRAVITREAL INJECTIONS. Sampling is also quite dependent upon batch performance . Manufactures were unsure of what "essentially free" meant. Data mining over a five-year period at the FDA Office of Generic Drugs suggests that the acceptance limits could be lowered, thus increasing drug safety without placing excessive burden on the industry. Both Ph.Eur. Particulate matter is defined in Particulate Matter in Injections 788 as extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in solutions. Both are generally accepted for use in testing large volume parenteral (LVP) and small volume parenteral (SVP) for the determination of sub visible particulate matter. Applying acceptance criteria, such as the criterion outlined in USP General Chapter <790>, is an important component of the overall visible particulate control program, but meeting these acceptance criteria alone is not sufficient to ensure compliance with the applicable CGMP requirements identified above, which cover a broader array of . Particulate matter consists of mobile, randomlysourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis due to the small amount of material that it . ware, membrane filter, and water are suitable for the test. This is not binding and is considered as an explanatory note to chapter "Visible Particulates in injections" which specifies conditions for visual inspection of visible particles in injectables. The subsequent acceptable quality level (AQL) inspection must be performed manually. Learning Objectives: Learn about the new demands in counting particles in liquids, with a focus on the challenges of preparing and sampling protein-based materials. . HIAC 9703+ liquid sampler and PharmSpec Software for Parenteral Drug Final Product Testing to USP<787>, <788> & EP2.9.19. tion with an appropriate diluent may be made to decrease USP <789> was established before the practice of intravitreal . Recent initiatives in guidance revision focus on the proper development and physical stability of the dosage forms as well. This consists of utilizing . USP <771> also establishes subvisible particulate matter limits based on two categories for product . The draft states that "the light intensity of the inspection station is also central to achieving maximum visibility. 11:35 a.m. Panel Discussion / Session I & II. The USP methods were initially developed for visible particulates and primarily intended for small molecule drug products. - Calculations for Apparatus E. Use q = (60/Q)x, where Q is the test flow rate in litres per minute, and x is listed in the table Cut-off diameter (m) x Mass of active substance deposited per discharge Cumulative mass of active substance For USP <788> the nominal test volume is 30mls. Why Particulate Matter in Ophthalmic Solutions? 1:05 p.m. - 5:00 p.m. 2.9.20 and USP uses a black and white background panel with observation times of at least 5 s against each background. The new USP <787> SUBVISIBLE PARTICULATE MATTER IN THERAPEUTIC PROTEIN INJECTIONS test can be used as an alternative to USP<788>. 20919 Particulate Contamination: Sub-visible Particles, JP 6.07 Insoluble Particulate Matter Test for Injections, and USP <788> Particulate Matter in Injections General Chapter can be used as interchangeable in the ICH regions given the following: . essentially free" standard is achieved when parenteral drugs are inspected and no more than a specified number of units are observed to contain visible particulates. Subvisible particulate matter tests include USP <787>,1 <788>,2 <789>,3 and <729>,4. the USP Workshop on the Control and Determination of (Sub)Visible Particulate Matter in Biologics, to be held at the USP Headquarters Meetings Center in Rockville, MD on June 26-27, 2017. An update to USP<1788> Methods for Determination of Subvisible Particulate Matter was released in May 2021. USP <788> places limits on the amount of sub visible particles that are allowed in injections. USP<790> Visible Particulate Specific lighting with different backgrounds Operators are trained and qualified White Background Black Background USP<787><788><789> Sub-visible Particulate No visible particles are allowed USP contains limits for sub-visible particles Method I: Light Obscuration Particle Count Particulate matter, visible or subvisible, in sterile parenteral products is regarded as a critical quality attribute, impacting safety of the product. USP <788> places limits on the amount of subvisible particles that are allowed in injections. The USP limits on particulate matter, harmonized with the European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP), are outlined in USP <788> "Particulate Matter in Injections". The best thing to do is monitor particulate matter throughout the clinical experience to ensure the presence of particulate is known and how it may change. Particulate matter is defined in Particulate Matter in Injections 788 as extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in solutions. Per USP Chapter <790>, all products must be visually inspected for the presence of particulate matter. 11/21/2016 33(2) Second Interim Revision Announcement: <788> PARTICULATE MATTER IN . Following publication of an initial draft Chapter. When examining injections and parenteral infusions for sub-visible particles Method 1 is preferably applied. Eur 5.17.2: Recommendations on testing of particulate contamination: visible particles. First Supplement to USP 37-NF 32 Physical Tests / 790 Visible Particulates in Injections 6393 Official from . Commentary Regarding new USP Chapters 787> and : 1787> for Particulate Matter Guidance: During the current (2010-2015) USP Expert Committee cycle, the Dosage Forms Expert Committee has developed both new and revised general chapters that provide guidance on particulate matter content of injectable drug products. For the determination of particulate matter, two procedures, Method 1 (Light Obscuration Particle Count Test) and Method 2 (Microscopic Particle Count Test), are specified hereinafter. PM is defined as extraneous mobile undissolved particles (excluding gas bubbles) that are unintentionally present in solutions.4 Several USP chapters describe the measurement of PM, namely: <787> Subvisible Particulate Matter in Therapeutic Protein Injections <788> Particulate Matter in Injections <789> Particulate Matter in Ophthalmic Solutions Manufacturers should consider container color, size, and shape as well as product characteristics when determining the . Particulate matter can change over time. Analysis and control of particulate matter are important aspects of the development of these drug products. Learn about the new test USP has recently posted for protein-based materials, known as USP <787>. Hi everyone, considering the monograph which is claimed to be included to USP 37 <790> VISIBLE PARTICULATES IN INJECTIONS, my company is confused in applying proposed requirements to powders for injections.These monograph is aimed to give concrete description of the "essentially free from particles" or "practically free from particles". The USP limits on particulate matter, harmonised with the European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP), are outlined in USP <788> "Particulate Matter in Injections". It is expected that both USP 788 methods 1 and 2 will be performed in Development, since one may need method 2 to decide batch release and the qualitative to quantitative information provided by retention of particulate matter is an invaluable aid for process improvement activity. This test. The initial 100% inspection can be automated, manual, or semi-automated. Visible particle testing per Ph.Eur. The benefit to the customer is, by using the small volume sub-visible particle adaptor test volumes can be reduced to between 1.5ml - 5mls, thus providing a cost saving to our customers and reducing sample sizes for small batch manufacture. The distributed vials from the affected lot are not being recalled due to shortages of this product. Particulate contamination: visible particles EUROPEAN PHARMACOPOEIA 6.0 Wet the inside of the filter holder fitted with the membrane filter with several millilitres ofparticle-free water R.Transfer to the filtration funnel the total volume of a solution pool or of a single unit, and apply vacuum. Its goal is to assist in the support and clarification of the information provided in chapters <787> Sub-visible Particulate Matter in Therapeutic Protein Injections, <789> Particulate Matter in Ophthalmic Solutions and <788> Particulate Matter in Injections. A Minimum Guideline for Manufacturers In August of this year, a new standard for visible particulate matterGeneral Chapter <790>became official in USP's compendia of public standards, U.S. Pharmacopeia National Formulary. . Extrinsic Particulate - Truly foreign or unexpected material (examples: metal or fibers) Intrinsic Particulate USP <790> defines "essentially free" as a batch of parental product that has been 100% inspected, meeting an AQL of 0.65% or tighter. 19 These standards outline the use of 2 procedures for particulate evaluation: the light obscuration (LO) particle count test and microscopy particle count test. USP <787> is meant for therapeutic protein injections, making changes for smaller test product volumes and smaller test aliquots. Particulate matter is defined in Particulate Matter in Injections 788 as "extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions.". . . Session III - Sub-visible and Visible Particulate Matter Determination . 4 This presentation will delineate the differences between the more well-known USP . 2. 11:10 a.m. Safety Evaluation of Particulate Matter . 342 788 Particulate Matter in Injections / Physical Tests USP 35 For preparations supplied in containers with a nominal ysis by either test method. Visible particles are defined as particles of size which can be seen by the unaided eye, typically in the range of 100 m and larger. The presence of foreign particulate matter contamination in parenteral drugs poses risks to patients and continues to be a leading cause of drug recalls (1)(2) (3) (4). For both methods, particles are extracted from the device with particle-free water (i.e . This general chapter provides an overview for the use of two procedures; Method 1, Light Obscuration Particle Count Test, and Method II, Microscopic Particle Count Test. Historically, we concentrated on control of extraneous particulate matter. Visual inspection is a probabilistic process, and the specific detection probability observed for a given product for visible particles will vary with . Recent FDA Warning Letters 8-30-2010 Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures The acceptance criteria is inadequate because your USP chapters provide alternate methods for determination of the inherent particulate character, as well as quantitation of unwanted particle types. All SUS bags examined contained measurable amounts of visible particles, of which textile fibers and cellulose particles were most commonly found in six out of eight products. The most referenced guidance comes from the USP, most notably in General ChapterInjections <1> and in <788> (although <788> generally deals with sub-visible particles). That is, drug these solutions can be automated, manual, or semi-automated observation times of at 5. 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