Limits are set for impurity levels as one of the steps in ensuring the identity, strength, quality, and chemical purity of drug substances. The ultimate goal is to produce a final drug product of high quality and at a reasonable cost that is safe and efficacious and remains so throughout its shelf life. The setting of limits for impurities in bulk drug substances is a complex process that considers a number of factors:
为杂质量制订一限度是确保原料药的同一性、浓度、质量和化学纯度步骤之一。最终的目标是生产出质量高、成本合理的制剂成品,并且这些制剂成品在整个货架期内始终保持安全性和有效性。对散装化学药品中杂质限度的制订是一个复杂的过程,需要考虑以下几点因素:
(1) the toxicology of a drug substance containing typical levels of impurities and/or the toxicology of impurities relative to a drug substance;
含有代表性杂质水平的原料药的毒理特性和/或与原料药相关的杂质的毒理特性;
(2) the route of administration, e.g., oral, topical, parenteral, or intrathecal;
给药途径,如,口服、局部用药、注射用药或膜内用药;
(3) the daily dose, i.e., frequency and amount (micrograms or grams) administered of a drug substance;
每日剂量,如,次数和服用的原料药的数量(微克或克);
(4) the target population (age and disease state), e.g., neonates, children, or senior citizens;
目标人群(年龄和病症),如,新生儿、儿童、或老年人;
(5) the pharmacology of an impurity, when appropriate;
如可行,杂质的药理学;
(6) the source of a drug substance, e.g., synthetic, natural product, or biotechnology;
原料药的来源,如,人工合成品、天然药物、还是生物技术加工品;
(7) the duration of therapy, i.e., administration over a long period (treatment of chronic conditions) versus administration intended for a short duration (treatment of acute conditions); and
治疗所持续的时间,如,服药周期长(对慢性疾病的治疗)与短期性服药(对急性疾病的治疗);
(8) the capability of a manufacturer to produce high-quality material at a reasonable cost to consumers.
生产商以合理的成本为消费者生产高质量的药品的能力。
Concepts for setting impurity limits in bulk drug substances are the concerns of the regulatory and compendial agencies as well as the pharmaceutical industry. The basic tenet for setting limits is that levels of impurities in a drug substance must be controlled to ensure its safety and quality throughout its development into and use as a drug product. The concepts are derived from issues and experiences with drug substances from traditional sources and technologies. Issues arising from biotechnologically produced drug substances, e.g., recombinant DNA and hybridomas, are still being defined and so are not necessarily covered by these concepts. However, the concepts can serve as a general foundation to address specific issues arising from biotechnology.
制订散装化学药品中的杂质限度是法规管理部门、药典机构和制药企业共同关心的课题。制订限度的基本理念是原料药中的杂质含量必须受到控制,以确保在药物制剂的研究和使用时的安全性和质量。此观念源于使用传统材料和技术生产的原料药的问题和经验。来自于使用生物技术生产的原料药(如,DNA重组和杂交瘤)的问题仍被定义,因此没有必要囊括在这些观念中。但是,观念可视作阐述生物技术引发的具体问题的一般基础。