Deficiencies in multi-purpose manufacturing site
ORANGE LETTER
Author:
PMDA Observed Regulatory Attention/Notification of GMP Elements LETTER
Issue: January 2025
Title: Deficiencies in multi-purpose manufacturing site
Source: https://www.pmda.go.jp/files/000273157.pdf
Related GMP Ministerial Ordinance Clause: Please refer to the detailed case.
1. Case
<Case 1: Deviation Management> (GMP Ministerial Ordinance, Article 15(1)(i)＆(ii) )
⚫ Though it is specified in the procedure that the deviation report should be created within one week after the deviation occurrence, the creation of deviation reports were always delayed for 2 or 3 months. Reasons for the delay were not confirmed and there were no record for it . In addition, there were many deviations for which CAPA (Corrective Action / Preventive Action) had not been taken.
⚫ For deviations which have not been closed, we instructed the manufacturer to give priority to the ones which may give impact on the products on the market and handle those deviations according to the procedure promptly. We also instructed them to investigate the reasons why deviation reports were not prepared in a timely manner, and to take necessary measures, such as strengthening progress management system.
(Japan / non-sterile preparation manufacturing site)
(Japan / non-sterile preparation manufacturing site)
<Case 2: Deviation control, management of procedures> (GMP Ministerial Ordinance, Article 15(1) (ii) and Article 8(1) (ii)
⚫ Granulation was carried out with a fluidized bed granulation dryer missing some parts. As CAPA for this deviation, revision of master procedures for parts installation and confirmation of all the equipment was planned. However, only the revision of procedure for the equipment missing parts and CAPA was conducted. Furthermore, actions extending to other equipment were not carried out.
⚫ We instructed the company to extract equipment that may have a similar deviation, extend actions to the equipment and also investigate why CAPA was completed while the initial plan was incomplete and took appropriate measures.
⚫ (Japan / non-sterile preparation manufacturing site)
<Case 3: Prevention of cross-contamination> (GMP Ministerial Ordinance, Article 8-2 and Article 9 (1) (i))
⚫ Although a master cleaning procedure for all the equipment had been established, cleaning procedures for each equipment were not created based on cleaning validation. For some equipment, detailed cleaning procedures had been created with pictures, but cleaning procedures were not created for over 100 pieces of equipment.
⚫ We instructed the manufacturer to investigate whether the previous cleaning procedures were appropriate, report the result and create verified cleaning procedures in writing.
(Japan/non-sterile preparation manufacturing plant)
(Japan/non-sterile preparation manufacturing plant)
<Case 4: Management of procedures> (GMP Ministerial Ordinance, Article 8(1) (ii) and Article 10(iii))
⚫ When manufacturing products which were not manufactured frequently, a personal notebook with notes on key points was brought to the site to confirm work procedures. There exists a risk that production is not conducted according to the latest procedures when referring to the personal notebook.
⚫ We instructed the manufacturing site to conduct improvements such as preparing records blank form with step-by-step instructions for production.
(Japan/non-sterile preparation manufacturing plant)
(Japan/non-sterile preparation manufacturing plant)
2. Catchword
Do you have the time to pay attention to each individual product or event?
✓ When dealing with multiple products, the workload of creating procedures, switching products, etc. increases a lot due to the sharing of manufacturing equipment and diversity of manufacturing methods. In addition, there is a possibility that the risk of trouble occurring and the risk of expansion of the impact on quality may increase.
✓ In particular, intensification in the workload may cause oversight and actions delaying, so whether there is resource shortages should be taken into consideration!
✓ Attention should be paid to whether the pharmaceutical quality system is effective enough to continuously and carefully monitor the occurrence of problems associated with multi-purpose manufacturing and assure that those problems are reported to the management, and the management are active to grasp the information on the production site so as to provide support to the production site.
✓ It is important to foster a corporate culture and individual awareness that prompt the entire company to take proactive measures in unison, rather than leaving it to the site when signs of resource shortages are seen! Once again, please keep on going with "quality first" mindset and daily, steady actions.
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