ORANGE LETTER
Observed Regulatory Attention/Notification of GMP Elements LETTER
The Orange Letter is a series of GMP survey findings that are considered particularly useful for the industry to be made known to the public, and will be published starting this fiscal year (2022) as a reminder and technical reference. The purpose of the letter is to encourage voluntary improvements in quality at each manufacturing facility and to strengthen management and supervision by manufacturers and distributors.
Issue: May 2022
Title: Risks associated with handling substances of unknown pharmacological effects and toxicity
Source: https://www.pmda.go.jp/files/000246593.pdf
Related GMP Ministerial Ordinance Clause: Article 9 Paragraph 2
1. Case
An investigational drug with unknown pharmacological effects and toxicity was manufactured in a workroom for manufacturing pharmaceuticals
2. Background
● It is defined in GMP Ministerial Ordinance that it is forbidden in principle to manufacture products to which the GMP Ministerial Ordinance "does not apply" in workroom for manufacturing pharmaceuticals
● Exceptions including (1) establishment of limit values for residue management based on scientific data (pharmacological and toxicological evaluations), (2) appropriate measures to prevent cross-contamination (verified processes, implementation of cleanup, etc.) are also defined, and sharing of work rooms is permitted under those conditions.
● The manufacturing site is a contract manufacturer, and the same equipment in the workroom that was used for manufacturing pharmaceuticals was also used for manufacturing investigational drugs (not subject to GMP ordinance) under contract.
3. Observations
● Information on the pharmacological effect and toxicity of the investigational drug contracted by the consignor had not been obtained.
● Limits for residue management based on scientific data had not been set.
4. Problems/Risks
● If the toxicity, etc. of substance that shares workroom or facilitie is unknown, there is a risk that appropriate residual limits may not be set and appropriate measures may not be taken to prevent cross-contamination.
● Pharmaceuticals may be contaminated by shared substance, and there is a risk of harm to the health of patients taking the medicines contaminated by the substance with toxicity.
5. Check Points
● When starting to manufacture a new product, have you got enough information on the product to handle with?
● Have you taken appropriate cross-contamination prevention measures (establishment of cleaning methods, removing methods, etc.)?
● As a manufacturing site, do you "understand the characteristics of substances" that share work rooms, etc., and have you taken measures to "remove" contaminations thoroughly?
6. Catchword
Recognize that the uncontrolled risks are ultimately borne by the patient taking the Drug !
◇ Even in contract manufacturing, it is important to take responsibility for the efficacy and safety of products shipped from one's own manufacturing facility. Risk caused by lack of information from the outsourcer should not be transferred to the patient!
◇ It is important to take measures to prevent unintended products from mixing into the pharmaceuticals.
◇ In particular, it is important to be able to explain with scientific evidence that the residual risk of the item is adequately controlled when the workroom or equipment is shared with other items.
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