PROCESS DEVELOPMENT AND CLINICAL PRODUCT MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 109

TABLE 6.4 Matrix for DOE of API Process
Parameter Low Range Mid Range High Range Units

Reactant 1 300 350 400 Kg

Reactant 2 500 550 600 Kg

Pressure N/A 1 1.2 Atmospheres

Mixing speed 60 80 120 Rpm

◦ C

Temperature Room temperature 60 120

Reaction time 60 120 240 Minutes

proven acceptable range (PAR) for each individual variable but also regarding
potential interactions between different factors. This information is then trans-
lated into batch manufacturing instructions that allow assignment of appropriate,
valid ranges to each parameter and successful manufacture of each batch as long
as each parameter is within its allowed range throughout the process. This will
ensure that the (C)QAs are met at the end of the process.
NOTE: Referring to the QTPP, one of the CQAs would include stability data at
the end of the product's shelf life, which is not included in a product specification
but is of course essential.
A similar matrix can be designed after using an Ishikawa to brainstorm possible
modes of failure of an analytical method under development (refer to Figure 6.4
and Table 6.5).

Preliminary risk assessment - where is the risk?

Machines Measurement

(Hu)man

Replace
HPLC with
GC / LC-
MS-MS

Enhance
skills for better
control of CPPs

SPC for CPPs

Preventive
maintenance SPC of reference

standard results

Train supervisor s
for oversight
duties

Analytical

Facility Chart deviations

SPC for
reference
standard

Replace
column

Daily improvement
program

Replace HVAC
to reduce dust

Repeatable and
reliable
(integrity)
of results

External expert(s)
provides new skills

Change
formulation

Interfering
substances

Microbial
controls

Characterization

Provide
training resources

Reference
standard

Fund PM
program

Column

Different
batches

CPPs:
Column
flow rate
Temp
Injection
volume
Other?

LOD / LOQ

Provide
resources

Reagents

Operating
parameters Age

supplier
water content
other

PM = Preventive maintenance

Materials Management

Methods

Figure 6.4 Ishikawa diagram for analytical method development. ( See insert for color
representation of the figure .)