ORANGE LETTER
Author: PMDA
Observed Regulatory Attention/Notification of GMP Elements LETTE
Issue: July 2022
Title: Overlooking Quality Risks Due to Inadequate CAPA
Source: https://www.pmda.go.jp/files/000247221.pdf
Related GMP Ministerial Ordinance Clause: Item (1), Paragraph 8 of Article 11
1. Case
Impact of OOS on other lots was not evaluated sufficiently
2. Background
● It is defined in GMP Ordinance that when the results of testing and examinations do not conform to the standards (OOS: Out of Specification), the cause must be investigated, and necessary corrective action and preventive action (CAPA) must be taken.
● It is specified in the procedure of the relevant manufacturing site that when OOS occurs, firstly the quality control department investigates whether or not there is a laboratory error, and if the cause of laboratory error is identified, the initial OOS result is rejected and retesting is performed.
3. Observations
● OOS that the upper limit of the content was exceeded when measuring the content of API X using titration method (Japanese Pharmacopoeia).
● Blank solution had not been cooled as preparing the sample solution, and this was concluded as the cause. Furthermore, when changing the preparation method of the blank solution and retesting, the result was within the specification. Therefore, the initial result was rejected, and it was judged as conforming. In addition, that the blank solution should be prepared and cooled was defined in the test procedure as a corrective measure.
● Though the measurement value shifted to lower one after cooling , the impact on the result of other lots tested without cooling had not been evaluated.
4. Problems/Risks
● In the past tests without cooling the blank solution, the measured value was overestimated, and API lot originally below the specification may be judged as conforming.
● API lots that are non-conforming may be shipped from the manufacturing site, which may affect the quality of finished products using those lots.
5. Check Points
● Have the causes of OOS been properly investigated?
● Have appropriate CAPAs been taken based on the identified root causes?
● Have the impact on other lots of products been assessed in addition to lot with OOS?
6. Catchword
Appropriate handling of OOS leads to “constant quality assurance of products distributed in the market”
◇ It is extremely to implement logical cause investigation based on appropriate risk analysis and CAPA when OOS occurs. In the case of OOS caused by test operations, etc., it is necessary to evaluate the impact on other lots tested by the same method.
◇ If the above measures are not inappropriately taken, it will lead to market distribution of lots that should be treated as non-conforming and finally affects patients!
◇ In order to prevent OOS caused by test operations, even in the case of using established test methods such as those defined in the Japanese Pharmacopoeia, it is important to take operations that affect the test into consideration during technology transfer and create appropriate test procedure.
About Author
Career The profile is the information as of the time of writing.
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