APR Nov/Dec 2022 - 22

»
DRUG DEVELOPMENT
»
Analytical Categories
Enantiomeric Control
Organic Impurities
Mutagenic Impurities (MI)
IPCs
Specification Related
Equipment Cleaning
Residual Solvents
Counter Ion
Key Raw Materials
Elemental Impurities
Form
Particle Size
Bioburden and Endotoxin
Poor Chromophores
Challenging Chromatographic
Selectivity
Physicochemical Related
LogP / LogD / pKa
Powder Properties /
Hygroscopicity / Viscosity
Method Robustness Concerns
Instrument Availability
Method Transfer Related
Consumable Availability
Unit Operations
Any
Any
LC / GC
LC / GC
Any
Inability to retain at mobile phase pH and / or inability to dissolve in compatible diluents
Materials difficult to accurately weigh and / or pipette
Poor method repeatability, stability, and / or narrow operating tolerances
LC / GC / CE / SFC / NMR Less common (GxP) instruments (e.g., SFC) and / or detection (e.g., LC-ELSD or GC-NPD)
Specialized and / or localized materials (e.g., small column vendors or single supplier derivatization reagents)
and / or availability of standards
Highly convoluted sample preparations with strict time limitations
Table 3. Examples of risk banding across analytical categories.
Risk Category
Enantiomeric Control
Method Performance Risk Band
Low
Isocratic method; target analyte(s) Rs
> 2.5;
LOQ < 0.1%; RSD of retention time and
response factor <<2.0%
Target analyte(s) Rs > 1.5; LOQ < 30% of
Specification Related
Mutagenic Impurities (MI)
specification; recovery > 80% and < 120%;
RSD of retention time and response factor
<<2.0%
Target analyte(s) Rs
IPCs
Poor Chromophores
(Organic Impurities)
Physicochemical
Related
Challenging Chromatographic
Selectivity (Organic Impurities)
> 1.5; LOQ << call
point; target analyte(s) retention times and
response RSD << 2.0 %
LOQ << specification; LC-UV > 220 nm
Target analyte(s) Rs
> 1.5 with any peak
in main peak tail > 2.0; peak purity check
passes; RSD of retention time and response
factor <<2.0%
Method Transfer
Related
Method Robustness Concerns
Phase appropriate validation completed
and all parameters met acceptance criteria;
successful transfer to at least one vendor
or other internal teams and / or tested on
multiple brands of instruments
Limit of quantification (LOQ). Relative standard deviation (RSD). Resolution (Rs
).
plans and methods. In order to maximize its adoption, the survey
workflow was designed to be simple, effective, and easily performed
(Figure 3). At a high level it is performed as a two-part process. In the
first part, the project team prepares the discussion materials while in
22 |
| November/December 2022
the second part, the project team presents to a team of analytical SMEs
and discusses the risk survey of the project to generate alignment
and possible follow-up activities. The overall workflow includes the
following major activities prior to the risk survey committee meeting:
Medium
RP gradient method; resolution
between 1.5 < Rs
< 2.5; LOQ < 0.15% or <
specification; RSD of retention time and
response factor < 2.0%
> 1.5, LOQ = specification; recovery >
70% and < 130%; RSD of retention time and
response factor < 2.0%
> 1.2; LOQ < call point;
Rs
High
NP gradient method; Rs
< 1.5; LOQ > than
0.5% or anticipated specification; RSD of
retention time and response factor > 2.0%
< 1.5; LOQ is higher than anticipated
specification; recovery < 70% or > 130%;
RSD of retention time and response factor
> 2.0%
Rs
Target analyte(s) Rs
target analyte(s) retention times and
response RSD < 2.0%
LOQ < specification; LC-UV >
210 and < 220 nm
Target analyte(s) Rs
> 1.2 with any peak
in main peak tail > 1.5; LC-UV peak purity
check passes; RSD of retention time and
response factor < 2.0%
Qualification completed and all parameters
met specifications; limited transfer activity
and / or limited alternate instrumentation
tested
Target analyte(s) Rs
> 1.0; LOQ = call point;
target analyte(s) retention times and
response RSD > 2.0%
LOQ = specification; LC-UV < 205 nm or
non-UV detection
Any target analyte Rs
< 1.2; LC-UV peak
purity check not performed; RSD of
retention time and response factor > 2.0%
Qualification completed and some
parameters only partially met
specifications; no transfer activities or
alternate instruments tested
Table 2. General risk categories for small molecule analytics
Higher Risk Examples
Typical Example
Techniques
LC / GC
LC / GC
LC / GC
LC / GC
LC / TOC
GC / LC
LC / IC / Titration
LC / GC
ICP-MS / OES
XRD
LLS
Bioassay
LC / GC
LC / GC
Poor resolution and / or sensitivity for enantiomeric pairs
Wide range of UV response factors affecting linearity and / or sensitivity
Sensitivity is not adequate for the specification and / or complicated sample preparation or detection
methods
Matrix incompatibility with common chromatography diluents and / or analyte stability
Poor solubility in reverse phase LC friendly solvents and / or low specifications (e.g., MI swab testing)
Class 1 solvents meeting 10% of ICH Q3C levels
Less common detection (e.g., LC-CAD or specialized electrode)
Thermally labile analytes with poor UV response
Challenging matrices (e.g., high salt formulations)
Difficult to process samples (e.g., extremely hard)
Uncommon presentations, such as nanoparticles or dispersions
High water content in last two steps of synthesis
Less common and / or non-linear detection
Regioisomers, diastereomers, and other closely related structures
APR Nov/Dec 2022

Table of Contents for the Digital Edition of APR Nov/Dec 2022
