Long-term stability of bevacizumab repacked in 1 mL polypropylene syringes for intravitreal administration

The following table sets out how this paper either does or does not comply with the NHS (UK) guidance on the assessment of stability for biological products. The table uses the NHS guidance section headings and numbering to assist the reader.

Study Design

NHS Guidance Property to Evaluate Criteria for Evaluation Compliant (Yes/No) Comment
5.2 Containers Non-PVC Yes
5.3 Storage Refrigerated in absence of light  Yes
Room temperature (25±2˚C)  No
5.4 Concentration Low & high clinically significant  N.A.  Single dose syringe
5.5 Storage period 48 hrs – 3 months  Yes
5.6 Sampling strategy At least 4 sampling points in addition to the baseline (T=0) data. No 3 sampling points in addition to T=0. Data only presented at 2 points.
For studies ≥6 months, monthly sampling up to 3 months, then 3 monthly until study end. N.A.
5.7 Sampling number Three independent batches Yes
Three replicates per batch Yes  20 syringes per batch
6 Testing protocol Minimum protocol to include:
a) color, clarity, particulate  No  Not performed
b) pH  No  Not performed
c) chemical stability  Yes
d) physical stability  Yes
e) sub-visible particles  Yes
f) biological activity  No  Not performed
g) Assessment of degradation  Yes  Results from a previous study used.

Storage at room temperature (5.3) was not assessed. Insufficient sampling points are taken (5.6). A number of analyses in the testing protocol (6a,b,f) are not included in the study.

Study Methods

NHS Guidance Property to Evaluate Criteria for Evaluation Compliant (Yes/No) Comment
7.1 Forced degradation A combination of some of: Previous study used
a) change in pH  No
b) realistic elevated temperature  Yes
c) exposure to UV light  Yes
d) agitation  No
7.2 Visual characteristics Color, clarity and particulates  No Not performed
7.3 pH Changes to pH  No Not performed
7.4 Sub-visible particulates Evaluate particle levels over necessary range (1 – 100 μm)  Yes
7.5 Physio-chemical analysis Range of techniques to assess conformational, physio-chemical and aggregates (below size in 7.4). Should comprise a combination of:
a) SEC  Yes
b) DLS  Yes
c) CEX  Yes
d) capillary or SDS electrophoresis  No
e) circular dichroism  No
f) FT IR  Yes
7.6 Chemical a) HPLC  Yes
b) UV  Yes
c) mass spectrometry  No
7.7 Biological activity Relevant to specific biological activity that enables product to achieve specific pharmaceutical action. Can comprise any of:   No No assessment of biological activity performed
a) biochemical (ELISA)
b) cell based
c) animal

Study Methods Summary

Visual characteristics (7.2) and changes in pH (7.3) were not assessed. Although electrophoresis (7.5d) and circular dichroism (7.5e) were not performed, the combination of other techniques employed is sufficient for a comprehensive assessment of physical stability. The combination of only HPLC (7.6a) and UV (7.6b) would not provide a comprehensive chemical characterization. Assessment of biological activity (7.7) is a key component of NHS guidance criteria to demonstrate the product achieves its specific pharmaceutical effect. No evaluation of biological activity has been performed.

© Maria Connolly & Andy Watts. Copies of this material can be made for the sole purpose of aiding in the assessment of the stability of the product presented in the study. Any copies must be made in full and retain this notice and the following reference to the NHS Guidance.

A STANDARD PROTOCOL for DERIVING and ASSESSMENT of STABILITY Part 2 – Aseptic Preparations (Biopharmaceuticals) EDITION 1 October 2012