The Importance of Particulate Cleaning of Packaging Components
Controlling Sub-visible Particles in Injections
When utilizing packaging components for parenteral drug products, it is critical to reduce particulate matter to acceptable levels through USP purified water and Water for Injections (WFI) rinses.
As the number of injectable drugs given to patients each year increases so does the concern about potential particulate matter that can be found in the drug. Particulate matter in injections is defined as extraneous, mobile, undissolved particles, unintentionally present in the end product (3). These contaminants can come from several sources such as the environment, packaging materials and formulation ingredients (5). Particulate matter can be extremely harmful when introduced into the bloodstream and can cause several adverse reactions in the patient such as vein irritation, local tissue infarction, anaphylactic shock and even death (1). Therefore, the United States Pharmacopeia places limits on the amount of sub-visible particles that are allowed in injections. The USP’s limits on particulate matter, harmonized with the European Pharmacopeia and Japanese Pharmacopeia, are outlined in the USP’s general chapter <788> “Particulate Matter in Injections.” The chapter contains the methods of determination of particulate matter in injections along with particle count limits for small-volume injections (SVI) and large-volume injections (LVI).
Pre-sterilization preparation of packaging components such asampules, vials, and rubber stoppers usually consists of a series of rinses with USP purified water and Water for Injections (WFI). These cycles are critical for removing foreign matter from the packaging components, minimizing the risk of patient harm from particulate matter.
All parenteral injections are sterile liquids and must comply with two limit tests for particle count. The first is USP <1> “Injections” which states that the product must be “essentially-free” of visible particles (2). The second is USP <788> “Particulate Matter in Injections” which states that only low amounts of sub-visible particle is acceptable within injectable drug products. The details of the limits outlined in <788> are found in Table 1: Current <788> Particle Limits.
Light Obscuration Method
The Light Obscuration Method counts particulate matter with the use of an electronic particle counter. The sample is drawn into the system with a needle where it passes through a light source and detector. At this point the light is either absorbed or refracted which will then generate a pulse. The magnitude of the pulse is dependent on the size of the particle. With this pulse a calibration curve is produced which will provide a qualitative and quantitative analysis of the particles in the sample. Diagram 1 provides a schematic of this process. As this is an automated process it eliminates operator error which makes it the preferred method for USP <788>.
Microscopic Particle Count
The second method illustrated in USP <788> is the Microscopic Particle Count Test where a compound binocular light microscope is utilized to count particles at 100X (3). First, the liquid sample is passed through a membrane filter with pore sizes ≤ 1 μm. The captured particles are then counted at 100x with a compound binocular microscope. This is a manual and operator dependent process which makes it prone to subjectivity. This method is usually utilized if light obscuration results are suspicious or failed the limit test.
Particulate Matter Classification
In general, any semi-solid to solid material may be counted as a particle and may be considered hazardous upon identification (5). Examples of such particles are air, liquid, gel, singular solid, aggregate, agglomerate, drug solid, salt, polymorph, lubricant and plasticizer. Three common types of particulate matter are extrinsic, intrinsic and inherent, described in table 2. It is critical to fully understand the identification, origin and characterization of particulate matter so the final product meets or exceeds the allowable particle count for USP <788>.
The sizes of particles vary within injectable drug products but are mainly classified into two categories which are visible and sub-visible. Visible particles are defined as those that can be detected under controlled conditions by the unaided human eye (1). Sub-visible particles are those that are ≤ 25 μm. The best-case threshold for the human visual identification is roughly 150 μm which makes the sizes between 25 μm-150 μm a visible gray zone illustrated in diagram 2. The sub-visible particle category ranges from submicron particle size up to the visible threshold which requires either the Light Obscuration Method or the Microscopic Method for particle counting for injectable drug products.
DWK Life Sciences Solution
When utilizing packaging components for parenteral drug products, it is critical to reduce particulate matter to acceptable levels through USP purified water and Water for Injections (WFI) rinses. A typical procedure is outlined in Table 3.
Cleaning must be done in a certified class 100/10 clean room with high-efficiency particulate HEPA filtering. HEPA are air filters that must satisfy specific standards of efficiency and remove 99.97% of particles that have a size larger than 0.3 μm from the air that passes through. When comparing USP purified water and Water for Injections (WFI) it is paramount to note that they must meet specific ionic, chemical and microbial requirements outlined in table 4.
Several different adverse reactions have occurred as a result of the injection of particulate matter (4). Therefore, particulate matter contamination is a real concern for the pharmaceutical industry. The consequences depend significantly on the size, shape, quantity, and composition of the particulate matter; therefore, a comprehensive understanding of the issue is a necessity to not only meet but exceed regulation requirements and to protect the health of the end-user of the final product.
- Gecsey, J., & Harrison, T. (2005). Sampling and preparation techniques key to success in meeting new requirements for particulate analysis in SVPs. European Journal of Parenteral & Pharmaceutical Science, 10(3), 79-82.
- General Chapter <1> Injections. USP 36/NF 31: United States Pharmacopeia. www.usp.org
- General Chapter <788> Particulate Matter in Injections. USP 36/NF 31: United States Pharmacopeia. www.usp.org
- Langille, S. E. (2013). Particulate Matter in Injectable Drug Products PDA Journal of Pharmaceutical Science and Technology, 67(3), 186-200.
- Singh, S. K. (2013). Particulate Matter in Sterile Parenteral Products. In P. Kolhe, M. Shah, & N. Rathore (Eds.), Sterile Product Development: Formulation, Process, Quality and Regulatory Considerations (Vol. 6, Advances in the Pharmaceutical Sciences, pp. 359-409). AAPS.
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