ORANGE LETTER
Author:
PMDA Observed Regulatory Attention/Notification of GMP Elements LETTER
Issue: January 2024
Title: Risk-based validation plan creating
Source: https://www.pmda.go.jp/files/000266618.pdf
Related GMP Ministerial Ordinance Clause: Article 13
1. Case
Risk assessment was not enough during validation.
2. Background
◆ The GMP Ministerial Ordinance stipulates that validation should be carried out when commencing manufacture of a new pharmaceutical at a manufacturing site; In addition, any rectification regarding production control or quality control is needed based upon outcome of the validation, the manufacturer, etc. must implement necessary measures.
◆ During commercial production, samples used for releasing testing should be taken from any one location within the lot.
3. Observations
◆ In the process validation (PV) of the tableting , the content, formulation uniformity, etc. were verified at three points: early (at the beginning of tableting), middle (when tableting is 50% complete), and final (when tableting is 90% complete). As the standards were met, it was concluded that the lot was uniform.
◆ However, no verification plan was prepared according to risks due to the product characteristics, manufacturing method, characteristics of the manufacturing equipment, etc., and for the relevant item (low-content formulation, direct tableting method), uniformity evaluation of tablets near the end of tableting (from 90% completion to the end of tableting), where there exists a risk of bias analysis, was not conducted.
4. Problems/Risks
◆ It is unclear whether tablets with uniformity and the specified quality have been manufactured right before the end of tableting.
◆ Even though the uniformity of the powder used for tableting has been assured, if the uniformity of the tablets within a lot after tableting cannot be assured, there is a risk that the quality of all the released products cannot be assured.
5. Check Points
◆ Whether necessary verifications have been conducted based on risk assessment that takes into account the product formulation, manufacturing method, manufacturing equipment, manufacturing scale, etc. and identification of factors that give impact to the uniformity before validation?
◆ Whether a sampling plan (location, frequency, method, etc.) is established to properly verify the uniformity within a lot?
6. Catchword
Have you identified all the factors that cause "dis-uniformity "?
✓ In the manufacture of tablets, granules, etc. that involves processing powder, bias analysis is promoted not only by characteristics (particle size, flowability, etc.) of powder and manufacturing method, but also by equipment (vibration, etc.), manufacturing time, manufacturing scale, powder handling (transportation, input, discharge, etc. of powder).
✓ If any factor that have a negative effect on uniformity is identified after verification taking into account the above factors, It is important to design a process to eliminate them through changing the equipment or the work method, or cutting off the dis-uniform part within the lot so as to achieve uniformity within a lot!
✓ Insufficient verification of uniformity within a lot would actually lead out of specification in stability monitoring. Reducing the risk of dis-uniformity in the manufacture of solid dosage forms directly reduces the risk of incidents that require action after market distribution!
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