ORANGE LETTER
Author:
PMDA Observed Regulatory Attention/Notification of GMP Elements LETTER
Issue: July 2023
Title: Handling of results related to stability studies
Source: https://www.pmda.go.jp/files/000263226.pdf
Related GMP Ministerial Ordinance Clause: No.1 Article 24
1. Case
Signs of quality defects were overlooked and countermeasures were not taken.
2. Background
◆ The following rules regarding stability monitoring are stipulated in the GMP Ministerial Ordinance.
(1) The target lots to be monitored and the packaging form of the product, etc. should be based on the identifying the quality risks and evaluation.
(2) Among the specifications of the selected products, items that are likely to be affected by storage conditions and items that are considered to affect efficacy or safety if they do not conform to the specifications (OOS: Out of Specification) shall be included in the testing items.
(3) If the test results show that there is OOS or there is a risk of OOS, necessary measures should be taken, such as promptly contacting the marketing authorization holder and providing information which is needed in determining whether the drug should be recalled.
◆ Stability monitoring is performed on “reprocessed” lots of drug substances with a retest period of 5 years.
◆ Results of purity tests (related substance A) of the drug substance tend to increase over time.
3. Observations
◆ The 48th month test results for related substance A reached close to the upper limit of the specification.
In addition, it turned out that there was a rapid increase in the last year which is different from the usual trend.
In addition, it turned out that there was a rapid increase in the last year which is different from the usual trend.
◆ However, because the results are within the specifications, the manufacturing site didn't conduct any investigation into the cause of the rapid increase in related substance A and they also didn't contact the authorization holder.
4. Problems/Risks
◆ Because it cannot deny that quality deterioration may be caused by factors other than changes over time, there is a risk that specifications may not be meet all over time until the retest date.
◆ If measures are not taken until OOS happens, there is a risk that products using APIs that do not meet specifications will be distributed to the market and used.
5. Check Points
◆ Whether the test results are within the specification, as well as whether there is any abnormal trend that should be confirmed have been defined in the procedure?
◆ Whether root cause investigation has been conducted when OOS may occur with the test results?
◆ Whether abnormal trend handling procedure has been in place and contacting MAH promptly has been defined?
6. Catchword
Noticing signs of unusual changes can help protect patients! !
✓ In recent years, there are sporadic cases of product recalls due to deviations from specifications during stability monitoring when the expiration date or retest date has not come up .
✓ If an abnormality in the trend occurs in a stability monitoring lot, it is necessary to evaluate the impact on the quality of the lot concerned as well as lots manufactured at the same time, lots subjected to the same process, etc. In addition, it is important to take measures before OOS actually occurs, such as confirming the trend ahead of the planned test day!
✓ Narrowing down the affected products which have been distributed to the market through the above activities will contribute to stable market supply!
About Author
Career The profile is the information as of the time of writing.
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