THE NEW CHANGES TO USP CHAPTERS FOR PARTICULATE MATTER GUIDANCE

   

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Broadly, cGMP regulations direct product design and assembly to exclude foreign matter and minimize foreign particle content. However, there is further guidance, in two general categories of particulate matter in several USP chapters that contain definitions, methods, and limits. These categories are visible particles, based upon human detection, and subvisible particles, based upon instrumental determination. While the major impact of particulate matter guidance is for sterile injectable products, there are chapters that address biotherapeutic and ophthalmic products.

USP guidance for particulate matter content in drug products is being reviewed and revised during the 2010-2015 revision cycle. Existing chapters

  • <1> Injections,
  • <788> Particulate Matter Determination,
  • <1788> Methods for Determination of Particulate Matter in Injections and Ophthalmic Solutions,
  • <789> Ophthalmic Solutions and
  • <771> Ophthalmic Ointments

will be revised, some extensively. Further, new chapters

  • <787> Subvisible Particulate Matter in Therapeutic Protein Injections and
  • <1787> Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections

provide guidance for protein therapeutic products.

Chapter <1> Injections and Implants

Along with the broad revision for USP sub <10> chapters, USP <1> is being extensively modified. Chapter <1> will be titled Injections and Implanted Drug Products (Parenterals)-Product Quality Tests, with guidance for drug product quality and drug product performance tests for injectable and implantable drug products. The most recent proposed revision appeared in Pharmacopeial Forum (PF) 39(5) Sep-Oct 2013. Specifically for subvisible particulate matter consideration, new USP chapter <787> and historical chapters <788> and <1788> are referenced; however, particle content limits have not changed. New chapters <771> and <790> provide guidance for visible particle content.

Contamination Control Strategies

Recommendation

Berlin, Germany5-7 November 2024

Contamination Control Strategies

Chapter <790> Visual Inspection of Injectable Products for Particulates

Chapter <790> is a new chapter that provides expectations and a benchmark for visible particle content. The final version of the chapter will appear in USP 38 First Supplement in March 2014, and becomes official August 1, 2014. The chapter provides a method for detection of visible particles and an acceptable quality level (AQL) percent defectives expectation at time of manufacture and throughout the shelf life of the product... Thus, the term "essentially free" of particulate matter has been explained in terms of an AQL level for particulate matter, categorized as a major defect.

Chapter <787> Subvisible Particulate Matter in Therapeutic Protein Injections

This new chapter appeared in PF 39(2) Mar-Apr in 2013. The final version will appear in USP 38 First Supplement in March 2014 and becomes official August 1, 2014. The chapter was developed to address deficiencies in <788> as it related to testing protein products and provides a testing framework for a scientific and regulatory concern for the immunological effects of sub-10μm particle populations. The chapter allows for smaller volume sampling (the standard 5mL down to 0.2mL), sampling of individual containers and gentler de-gassing steps. The historical <788> limits are retained; however, attention to the sub-10μm particle load is recommended. Finally, total particle content is limited to 6000 ≥10μm and 600≥25μm for all dose forms.

Chapter <771> Ophthalmic Products

A revision to <771> considers the addition of product quality tests for all ophthalmic dosage forms, as well as ointments. Chapter <751> Metal Particles in Ophthalmic Ointments is being deleted from the compendia. General Chapter <771> will now contain cGMP-based guidance for general particle quality expectations for all ophthalmic dosage forms, their design, and their assembly.

Chapter <788> Particulate Matter in Injections

There are two changes that are being proposed to the harmonized particulate matter chapter:

  • Total particle load limit for Large Volume Parenteral products
  • Individual container testing regardless of fill volume

New specification for Large Volume Parenteral (LVP) Products

The current version of USP <788> has different limits for Small Volume Parenteral (SVP) and LVP products, with SVP products having per container limits and LVP products per mL limits. Given LVP volumes, particle load in largest volumes could exceed single container SVP loads. For example, any LVP above 240mL could exceed the SVP ≥10μm limit and be acceptable based on current LVP limits:

  • SVP: At a limit of 6000 ≥10μm/container and 600 ≥25μm/container, all container counts equal total load
  • LVP: At a limit of 25 ≥10μm/mL and 3 ≥25μm/mL,
    -> at 200mL total load equals 5000 ≥10μm and 600 ≥25μm; meets SVP limit
    -> at 240mL (and above) total load equals (or exceeds) 6000 ≥10μm and 600 ≥25μm; exceeds SVP limit

Since several liters of LVP products are often administered intravenously during a single hospital stay, the total particulate load administered via LVP products can be several times greater than that administered via SVP products. The risk to the patient is compounded by administration often to critical care patients with compromised immune system and/or organ function. Thus, we have proposed a ceiling (container-based) limit for LVP's similar to that of SVPs:

  • limit of 6000≥10μm/container and 600≥25μm/ container

Also the above proposed limitation for LVP's has been adopted in USP new General Chapter <787> Subvisible Particulate Matter in Therapeutic Protein Injections which will become official August 1, 2014.

Proposed Language addition

Chapter <788> requires pooling the contents of 10 or more containers for SVPs less than 25mL and allows single container analysis for SVPs 25mL and greater. Historically, samples must have 25mL volume, required for light obscuration (LO) analyses. The basis of the requirement is to provide 25mL of a test sample for 4 x 5mL sampling in the LO instrument. The microscopic test currently requires pooling the contents of 10 or more containers for SVPs less than 25mL as well; however, this requirement is not necessary for MM, since with this method one can determine particle load on an individual container, regardless of the container volume. This is now valid for certain LO instruments which can accommodate smaller volumes, down to 0.2mL. So a requirement to provide 25mL of test sample for LO is unnecessary for those systems.

Risk Assessment in Contamination Control

Recommendation

Berlin, Germany8 November 2024

Risk Assessment in Contamination Control

USP is proposing the allowance of per container sampling of 10 or more containers to comply with the guidance requiring 10-container pools. We are not limiting the batch assay to just one container. Using singular containers in a sampling of many allows determination of particle load variation. Pooled samples may still be used. It would be up to the manufacturer to sample and test according to a defendable statistical plan and represent the results to the appropriate regulatory body. We propose to allow the analysis of single units or pooling for SVP samples, for both methods.

Author:
The biologist Scott Aldrich from Ultramikro LLC, USA, is an active Member of the 2010-2015 USP Dosage Forms Expert Committee, mainly for Injections; USP Chapters < 1 >, < 788 >, < 789 > and others.

Literature
Madsen RE, Cherris RT, Shabushnig JG and hunt DG. Visible Particulates in Injections - A history and a Proposal to Revise USP General Chapter Injections <1>, Pharmacopeial Forum 35(5) Sep-Oct 2009, 1383-1387.

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