APR May/June 2023 - 14

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MANUFACTURING
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*
" It is generally considered acceptable that a minimum of three
consecutive batches manufactured under routine conditions
could constitute a validation of the process " .
*
" An alternative number of batches may be justified taking into
account whether standard methods of manufacture are used
and whether similar products or processes are already used at
the site " .
Based upon this we update the baseline number of batches to N=3,
(see Table 2).7
Knowledge
Table 1. N= 3 Risk Evaluation Table
Risk
Low Level of Knowledge
High Risk
Moderate Risk
Typical / Average Level of Knowledge
Low Risk
High / Very High Level of Knowledge
Consider additional development or preparation
activities. Leadership approval to start PPQ with risks
detailed. Prior to proceeding to PPQ
PPQ: N = Baseline = 3
PPQ: N ≤ 3
It is important to note in this approach increasing the number of
batches does not occur when there is low knowledge and high risk.
This may be counterintuitive. Increasing the number of batches
does not lower risk, it increases it for the PPQ. If the knowledge level
places us at the high-risk level, we would expect some risk control
activities to be executed to lower risk. Including more work to increase
product knowledge, or in cases like pandemic vaccines, get leadership
approval to initiate PPQ. This will come with an acknowledgement of
risk, including a risk benefit analysis (RBA).
High Level Approach
A high-level summary view of the approach is provided below. In
practice, expect a multi-page risk check list or a very detailed decision
tree. Figure 1 is for visualization purposes only, however it should be
noted this approach has been used on Aseptically Filled Drug Product,
ATMPs, and Biologics Drug Substances.
There are three basic steps to the rules-based approach as shown in
Figure 1.
Step 1: Determine the baseline number of batches using product
and process knowledge.
* The level of product and process knowledge are used to
determine the minimum number of batches (or baseline) that
need to be produced during PPQ.
* Answers to the questions provide guidance to one of three
rules-based starting points for " N " number of batches. As
product and process knowledge increases the potential starting
point for the selection of the number of batches decreases.
A risk evaluation table is used to guide the determination
(Table 1).
Step 2: Determine if any additional controls, activities, or technical
rationales are required.
* This is our risk control step.
* Step 2 helps to confirm the selection of the number
of batches from Step 1 and determines specific site
level knowledge.
* Risk control activities determine if additional studies or batches
need to be performed/executed.
Step 3: Determine if there are any related risks/sources of
knowledge such as, business, technical, or strategic justifications
for the addition of batches above that set in steps 1 and 2.
* Additional rounds of questions may be asked to determine
if the number of batches needed to support PPQ should be
increased based upon business or strategy, in addition to risk.
* These should be rules-based as well.
* After Step 3, the number of batches, N, is provisionally set.
Figure 1. High Level Rules-Based Selection Decision Tree
Figure 2. Case 1 New Product: Rules-based QRM selection of
Number of Batches (N=3)
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| May/June 2023
APR May/June 2023

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