Untitled Quiz

Establishing Biologics Reference Standards

• The process outlines the establishment and maintenance of biological reference standards for pharmaceutical products, specifically addressing biological activity (potency).
• The document focuses on the production of a biological reference standard, with sections detailing manufacturing, quality control, quality release, and potency assignment.

Manufacturing

• The production starts by receiving quality released bulk or final container material (e.g., human coagulation factors).
• A specific master batch record is created for the reference standard.
• The material is then concentrated, diluted, lyophilized, formulated, and filled.

Quality Control

• The reference standard undergoes several tests, including lot homogeneity, solution stability, accelerated degradation studies, and potency assignment against the actual reference standard.

Quality Release

• A certificate of analysis (CoA) is generated for the reference standard.
• The standard is released by the Standards and Reagents Services Department as a control standard.
• The potency of the new reference standard is assigned through calibration against a primary standard (established by WHO).
• The product information includes the assigned activity of the newly created reference standard.

Potency Assignment

• The calibration protocol aims to ensure the accuracy of the reference standard.
• The primary standard (WHO) is considered accurate by definition.
• Secondary standards are calibrated against the primary reference standard, resulting in 100% accuracy for their activity.
• Accuracy of the reference standard is defined as the difference between experimental results and the assigned potency.
• In cases where the reference standard is used for different test systems and results vary significantly, a "compromise" potency value is assigned with accepted inaccuracies across all systems.
• If the difference is too high, a potency is assigned for each test system individually.
• By assigning potency, the accuracy of test systems can be optimized:
  • If a test system consistently produces lower results (e.g., 85% recovery), it is considered to have lower accuracy.
  • Similarly, test systems showing consistently higher results (e.g., 115% recovery) have higher accuracy.
  • Assigning potency based on the mean value of the different test systems optimizes the overall accuracy.

Performance of the Calibration

• Calibration utilizes 4-6 dilution levels encompassing the working range.
• The test design follows regular inter-laboratory exercise design, utilizing various samples including:
  • Primary standard
  • Old and new in-house reference standard
  • In-house control standard
  • Product samples with different matrices
  • Different reagent lots

Evaluation of Calibration Results

• Results from different reagent manufacturers, labs, and equipment are compared using t-tests or ANOVA.
• The analysis identifies significant differences, ensuring the robustness of the results.

Assignment of Activity (Potency)

• The assigned potency is calculated using the arithmetic mean of experimental results from calibrating the new reference standard against the primary (WHO) standard.
• The potency assignment is documented, including:
  • Reference standard lot number and assigned value
  • Test systems and laboratories used
  • Information on potential product result shifts
  • Date of calibration
  • Timeline for transitioning to the new standard

Changeover Documentation

• When changing to a new reference standard:
  • The date of the changeover is documented.
  • Laboratories and the product release department are notified about the change, usually two weeks prior.

Calibration Report

• This report includes potency assignment documentation, re-calculation of activity of stored bulk material (based on the old and new assigned potency ratio), and potential retesting of stored bulk material using the new reference material.

Release of New Standard

• The release of the new reference standard (with its newly assigned activity) is handled by the Standards and Reagents Services Department.