Oral solutions are susceptible to contamination during production and use. If sweeteners such as sugar are included in the prescription, microorganisms are prone to breed. Lannett Company of the United States recalled its product levetiracetam oral solution in 2019 due to contamination by Bacillus subtilis [4]; FDA review reports on propranolol oral solution and enalapril maleate oral solution Both require detection and establishment of control strategies for Burkholderia cepacia.
The control points of the quality management system of drug research and development and the possibility of using Bacillus subtilis group in commissioned research and development and registration application to endanger health depends on factors such as the degree of microbial contamination, the dose and duration of treatment, the underlying condition of the patient, and the immune function. Serious infections may develop in low-lying patients. Burkholderia cepacia is widespread in soil, plants, and humans, can be transmitted from person to person, and is prone to infection in immunocompromised patients (such as those with cystic fibrosis and chronic granulomatous disease), And resistant to a variety of chemical antibacterial agents [5]. The survey found that Burkholderia cepacia was detected in the purified water used in drug production and in the samples of treatment clinics, and it was the most detected pollutant. In May 2017, the FDA issued a statement informing drug manufacturers of the risk of contamination of the Burkholderia cepacia complex in non-sterile aqueous matrix formulations [6]. In September 2021, the FDA released the draft industry guidance "Microbiological Quality Considerations in the Production of Non-sterile Drugs" [7], which elaborated on the adverse effects of non-sterile water-based drugs caused by Burkholderia cepacia and other microbial contamination. Events, Risks and Controls. Chapter <60-62> of the United States Pharmacopoeia (USP 2022) elaborates on the Burkholderia cepacia complex test, microbial enumeration test, specific microbial test, etc.
The Center for Drug Evaluation (CDE) published in the "Pharmaceutical Common Issues and Related Technical Requirements of the Pre-marketing Application Meeting of Chemical Drug Innovative Drugs" and "Pharmaceutical Common Issues and Related Technical Requirements of the Pre-Phase III Clinical Trial Meeting of Chemical Drug Innovative Drugs (Draft for Comment)" Both require the reference to the relevant technical requirements to conduct research on Burkholderia cepacia and formulate corresponding control strategies [8-9]. For oral solutions for children, in addition to the microbial limit inspection and control in accordance with the four appendices of ChP 2020, inspection and control of Burkholderia cepacia is also required.
ChP 2020 Four General Rules 1107 "Microbial Limit Standards for Non-sterile Drugs" clearly requires inspection of other potentially harmful microorganisms that may exist based on factors such as the characteristics and uses of raw materials and their preparations, and preparation production processes. The applicant can assess the risk of introducing Burkholderia cepacia into pharmaceutical water, etc., and include it in the release quality standard or registration standard.
Oral solutions are non-sterile preparations. For multi-dose oral solutions, it is necessary to simulate the actual clinical use and investigate the stability in use. The inspection items include physical and chemical stability, microbial limit, etc. Research samples are proposed to include final stability test samples. According to the research results, the stability information in use is listed under the corresponding item in the instructions to guide clinical rational drug use.
28mm child resistant cap for liquid medicine
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