The half-life of a drug determines how long it stays in the body, and a drug with a short half-life can be compensated for by shortening the dosing interval and increasing the dosage administered, but there are cost and safety as well as compliance limitations. Those peptide drugs that have received regulatory approval have significantly higher plasma half-lives of the drug compared to endogenous peptides, providing us with success stories of increasing the in vivo stability of peptides from minutes to hours or longer. Peptide drugs use different chemical structure modification strategies to retard blood or tissue protease-mediated degradation and inactivation, thereby enhancing the drugability of peptide drug candidates.

In April 2022, the CDE published Technical Guidelines for Pharmaceutical Research and Evaluation of Biosimilar Pharmaceuticals for Insulin-d Products. Although the scope of application of this guideline is clear for the seven biosimilars of insulin-d products expressed and prepared using recombinant product technology, in fact, the nature of modern drug R&D and production should be d on scientific (data) and risk management, aiming to ensure the safety and efficacy of the drug, so for the biosimilars of other recombinantly-expressed peptide-d drugs can be referred to this guideline.

Small molecule modifiers are described in the guidelines as follows:

I.Starting raw materials

2. Small molecule modifiers

Small molecule modifiers are one of the important factors to change the pharmacokinetic behavior of insulin-d products. The potential impact of their quality on product safety, efficacy and quality controllability can be fully assessed d on their structural features and preparation process, focusing on the ability to control impurities, such as degradation products, isomers, genotoxic impurities, organic solvents and elemental impurities. Determine the preparation process or supplier of small molecule modifiers as early as possible to ensure consistent quality from batch to batch as well as the representativeness of samples in clinical trials.

2.1 Manufacturing process

If small molecule modifiers are produced in-house, the selection of starting materials for the preparation should refer to ICH Q11 and related technical requirements, and reasonable internal control standards should be established; reasonable control standards should be formulated for key process intermediates.

  2.2 Structure verification

Reference can be made to the requirements of the “Technical Guidelines for the Preparation and Structure Verification Studies of Chemical Drug APIs” and other requirements, combined with the process route, a variety of analytical testing methods can be used to carry out structural studies on the chemical structure of small molecule modifiers, and for the small molecule modifiers containing stereo configurations, single-crystal X-ray diffraction and nuclear magnetic resonance can be used to carry out the stereo structure verification studies.

   2.3 Quality standard

According to the requirements of insulin product quality control, combined with the preparation process of small molecule modifiers, the control items, methods and limits of small molecule modifiers quality standards should be reasonably formulated. For potential genotoxic impurities, risk assessment and control can be carried out according to the requirements of ICH M7.

2.4 Stability

Reference should be made to ICH Q1A (R2), Q1B and the “Chemical Drugs (APIs and Preparations) Stability Study Technical Guidelines” to conduct relevant studies, and formulate reasonable storage conditions and re-examination period.

    Chengdu Pukang Biotechnology Technology Co., Ltd. focuses on the R&D and production of peptide side-chain modifiers. All of the company's simethicone series side-chain modifiers are subject to pharmacological studies with reference to the research requirements of APIs, and the impurity profiles have been evaluated and controlled in detail, and if necessary, we can cooperate with our customers for the validation of impurity removal in the subsequent process of using the modifiers, in order to formulate a more reasonable quality standard of the modifiers, and write the DMF documents with reference to the requirements of ICH M4. At present, DMF documents have been completed for the main varieties of the side-chain modifiers of the Simeglutide series of the company, and some of them have been declared (FDA filing or declared by the domestic customers as an attachment to the CDE). The company's production has established quality management system with reference to GMP and ICH Q7. At present, all the main varieties of this series have completed process validation in the factory and have sufficient capacity to meet the needs of commercialization of customers' drugs.