Biologic Documentary Standards in Pharmacopieal Forum

PF 42(5) (Sep-Oct 2016) Comment deadline: Nov 31, 2016 

  • <509> Residual DNA Testing [NEW] (briefing follows, read complete text in Pharmacopieal Forum)

    During the manufacture of biopharmaceuticals produced in cells, residual host cell DNA must be minimized as much as possible; therefore, demonstration of host cell DNA reduction or removal is required during in-process testing or at release. This proposed new chapter provides a validated method suitable for measurement of residual host cell DNA in recombinant therapeutic products produced in either Escherichia coli or Chinese hamster ovary (CHO) cell lines. The chapter also includes an optional extraction procedure that is suitable to be used prior to a quantitative polymerase chain reaction (qPCR)-based method for the measurement of residual host cell DNA.

  • Fondaparinux Sodium (View PF Online)

The following revisions are proposed. The impurities and other test specifications are from the FDA-approved manufacturers. It is proposed to revise the monograph as follows:

  1. The Assay has been revised to add instructions to filter Solution B, revise the Note in the Assay to include further suggestions on obtaining a stable baseline, a System suitability solution B subsection and related RS have been added, and wording on the resolution requirement has been added for clarity.
  2. A hyperlink to the nitric acid reagent has been added in the test for Sodium Determination.
  3. The test for Organic Impurities has been revised to specify solutions to be used in the test and include a Note explaining USP's approach to Fondaparinux-related impurities as well as process-related impurities from the synthesis. The section now includes degradation impurities as well as process-related impurities above the unspecified impurity limit.
  4. The test for Water Determination has been revised to include a Sample amount and detailed Analysis. 

The  following revisions are proposed. The impurities and other test specifications are from the FDA-approved manufacturers. It is proposed to revise the monograph as follows:

  1. The Assay has been revised to include an additional dosage form in the acceptance criteria, add instruction to filter Solution A and Solution B, and to revise the Note in the Assay to include further suggestions on obtaining a stable baseline.
  2. The test for Organic Impurities has been revised to include a Note explaining USP's approach to Fondaparinux-related impurities as well as process-related impurities from the synthesis. The section now includes degradation impurities as well as process-related impurities above the unspecified impurity limit. Previously missing structures of impurities are now provided. Specimen chromatogram was revised to typical chromatogram.
  3. The Bacterial Endotoxins Test limit has been revised to NMT 33 USP Endotoxin Units/mg of fondaparinux sodium.

The  following revisions are proposed:

  1. The Definition section is revised for clarity.
  2. In Identification B, the Injection volume of 100 µL is revised to 50 µL to align with the current European Pharmacopoeia monograph.
  3. The time for the Loss on Drying test is revised from 16 h to 24 h to align with the current European Pharmacopoeia monograph.
  4. The title of Impurities is revised to Product-Related Substances and Impurities and the title of Related Proteins is revised to Product-Related Substances, based on the recommendation from the USP Biologics Monographs 1–Peptides Expert Committee.
  5. The Labeling section is revised for added clarity.

The following revisions are proposed:

  1. In the Definition, the text “is available as an acetate salt form” is removed because it is not needed.
  2. In Identification A, “major” peak is revised to “teriparatide” peak for added clarity.
  3. A cell-based bioidentity test is added as Identification C.
  4. In the Assay, the wording of “approximately” is removed from the preparation of the Standard solution.
  5. In the test for Product-Related Impurities, the information for the relative retention time of the first post-main peak (related to the teriparatide peak) is included.
  6. The specification for the Bacterial Endotoxins Test is revised for added clarity.
  7. The specification for the Microbial Enumeration Tests is revised and a reference to Tests for Specified Microorganisms <62>  is added for additional clarification.

The following revisions are proposed:

  1. To address that the drug product can contain a preservative, text reading “The formulation may contain a suitable preservative”, is added to the Definition. In addition, the text “excluding peaks due to added preservative(s) or excipients”, is included in the Analysis section from the test for Product-Related Impurities.
  2. In Identification A, “main” peak is revised to “teriparatide” peak for added clarity.
  3. A cell-based bioidentity test is added as Identification B.
  4. The liquid chromatographic procedure in the Assay and the test for Product-Related Impurities is based on analyses performed with the Zorbax 300SB-C18 brand of column with L1 packing. In the Assay, the retention time for the teriparatide peak is approximately 8 min.
  5. In the Assay, the word "approximately" is removed from the preparation of the Standard solutions.
  6. In the test for Product-Related Impurities, the preparation of the System suitability solution is revised based on additional information received. The information for the relative retention time of the first post-main peak (related to the teriparatide peak) is also included.
  7. The specification for Bacterial Endotoxins Test is revised for additional clarification. 

PF 42 (4) (July-Aug 2016) Comment deadline: Sept 30, 2016  (PF posts July 1) (View PF Online)

Because there is no existing USP monograph for this drug substance, a new monograph based on validated methods of analysis is being proposed. The liquid chromatographic procedures in the Assay and Product-Related Substances and Impurities, Procedure 1are based on analyses performed with the Phenomenex Synergi Max-RP C12 brand of L87 column. The typical retention time for eptifibatide in the Assay and Product-Related Substances and Impurities, Procedure 1 is between 33 and 37 min.