On June 19, 2023, CPHI & PMEC China 2023, an event showcasing advanced pharmaceutical products and medical devices, kicked off at Shanghai New International Expo Center. As CPHI China’s partner, BaiPharm staged a seminar “Application of Computational Toxicology in the Pharmaceutical Industry” which covers four sessions, each presented by experienced experts.
The experts shed light on how to conduct impurity study and set health-based exposure limits (HBEL) for manufacture in shared facilities. The following are summaries of the four sessions where the experts offered advice to drug marketing authorization holders (MAHs), manufacturers, and other stakeholders.
1. (Q)SAR for Genotoxicity Assessment in Compliance with ICH M7 Guideline
Mr. Yayun Sheng speaks at CPHI China & BaiPharm event.Yayun Sheng, senior application engineer at Cloud Scientific, noted that authorities were improving the requirements for studying mutagenic impurities with potential carcinogenic risks. He had met with corporate clients that had to conduct supplemental studies under the stipulation of authorities which found the companies’ genotoxic impurity controls incomplete.
To prevent the review timeline getting longer due to supplemental studies, Mr. Sheng advised companies to utilize the model of Quantitative Structure Activity Relationships, abbreviated as (Q)SAR, to identify high-risk carcinogenic impurities. With the aid of (Q)SAR model, companies can make impurity study & control more reliable.
2. Toxicological Assessment of Genotoxic Impurities
Mr. Xiaochun Yang speaks at CPHI China & BaiPharm event.Xiaochun Yang, associate professor at Zhejiang University, elaborated genotoxic impurities and ICH M7 Guideline Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.
Genotoxic impurities, also known as genotoxic impurities, refer to impurities that cause DNA mutations (deletions, insertions, and base substitutions), DNA recombination, and chromosomal aberrations. For genotoxicity study, usual methods include the Ames test, chromosomal aberration test, micronucleus test, and other approaches such as mouse lymphoma gene mutation test, comet assay, Pig-a gene mutation assay, etc.
ICH M7 Guideline focuses on mutagenic impurities, which are identified by the Ames test. The recommended combination for the Ames assay is an in vitro mammalian cell assay plus an in vivo micronucleus assay.
Mr. Yang noted that repeated dose toxicity test was the core of drug non-clinical safety evaluation. He reminded companies to pay particular attention to the following five points in the evaluation.
1) Predict the clinical adverse reactions that may be caused by the test substance. The prediction includes the reactions’ nature and strength, dose-response relationship and time-response relationship, as well as reversibility, etc.;
2) Identify the target organ/tissue subject to the toxicity of the repeated dose of test substance;
3) Deduce the starting dose for clinical trials and the safe range of repeated dose;
4) Note the key monitoring indicators for clinical trials;
5) Provide reference for detoxification or rescue measures in clinical trials.
3. Strategy for Nitrosamine Impurity Control
Mr. Jiaqiang Guo speaks at CPHI China & BaiPharm event. Since nitrosamine, a carcinogen, was discovered as an impurity in valsartan in 2018, authorities have paid more attention to identifying and controlling such impurities. According to BaiPharm technical expert Jiaqiang Guo, nitrosamine’s study and control are quite different from those of mutagenic impurities. For example, unlike general impurities, nitrosamine impurities cannot be controlled with the Ames test. Instead, the total nitrosamine impurities in chemical drugs can be controlled with the assessment of total exposure amount or total excess risk of cancer.
Mr. Guo also mentioned that nitrosamine impurities can exist in the manufacture of active pharmaceutical ingredients, the storage of preparations, and unexpected pollution in manufacture. He suggested companies should keep a close eye on the relevant guidelines and regulations to meet the requirements for identifying and controlling nitrosamine impurities.
4. For Manufacture in Shared Facilities: HBEL Formulation Strategy and PDE Calculation Difficulties
Ms. Wenjuan Li speaks at CPHI China & BaiPharm event.China CFDI recently issued the Quality Risk Management Guidance for the Manufacture of Different Medical Products in Shared Facilities (hereafter referred to Guidance) to reduce the contamination and cross-contamination in products that share manufacturing facilities. The active substance residue limit mentioned in the Guidance should be established based on product toxicity test data or toxicology literature, in combination with actual production conditions, and be regularly evaluated during the product life cycle.
For calculating the limits, BaiPharm regulatory affairs expert Li Wenjuan recommends HBEL / Permitted Daily Exposure (PDE) / Acceptable Daily Exposure (ADEs). According to her, PDE/ADE calculations can be adopted directly if effective, reliable, and sufficient pharmacological/toxicological data are available; if unavailable, cross-reference (read-across), (Q)SAR and Threshold of Toxicological Concern (TTC) can be used for setting PDE/ADE.
Ms. Li also reminded companies that they should provide a complete HBEL (PDE/ADE) report, instead of a mere number.
Q&A
For audience’s questions, the experts gave their answers as follows.
Yes. It should also be noted that HBEL needs to be periodically reassessed during the life cycle of the product based on toxicological and/or pharmacological data.
The person should have sufficient professional knowledge and experience in toxicology/pharmacology, and have extensive experience in drug-related fields and PDE assessment.
It is unacceptable that a manufacturer merely purchases an assessment report without conducting a suitability assessment.
The service provider should offer a complete HBEL assessment to the client, or provide data for the client to conduct HBEL assessment.
During the inspection of the manufacturer, the experts who carry out the HBEL assessment should be present on site or be contacted in time.
In the case of producing multiple drugs in shared facilities, if pharmacological and toxicological data are available, stakeholders should ensure that the active ingredient residues can be detected based on the data, and the detection method should be adequately sensitive.
If the residue’s hazard level is high, the cleaning process can decrease the residue to the degree that is below the acceptable limit, the detection method is effective, and necessary control measures are taken, then the contamination and cross-contamination produced the manufacturing process with shared facilities can be deemed under effective control.
Ask BaiPharm if you need support for HBEL/PDE/ADE report.
