INVENTOR 公司和较大的仿制药/非专利公司外包一些 AI 和中间体的制造，他们有专家团队确保供应链管理到位，以确保已经在研发和注册开发方面进行的巨额投资。对来料制造商进行严格的评估和后续审计，涉及表 1 中突出显示的主要领域。
通常，委托制造商将获得中间体以进行反应，并且此类中间体的质量将得到保证。
For the purpose of this article, the term “marketing company” is used to define those companies that:
â– Register finished products in national and regional markets
â– Are not involved in discovery of new active ingredients (AIs)
â– Do not manufacture agrochemical AIs
â– Purchase AIs and/or finished formulated products
â– Sell finished formulated products to the distributor network.
Marketing companies invest considerable effort and resources into obtaining registrations and getting a product to market but tend to spend very little effort on supply chain management. Their main focus is on technical specification, documentation required for registration purposes (five batch analysis, field trial data, etc.) and delivery schedule for timely market entry once the registration has been achieved. A typical marketing company does not understand the process of manufacture of the AI and, as a result, is at great risk that the supply of AIs might be disrupted for a variety of reasons including:
â– Lack of access to a key raw material
â– Restrictive process patents
â– Lack of capability to test quality of product
â– Supplies of the AI and/or key intermediate being bought out by the inventor company and
â– Loss of manufacturing licenses for environmental reasons.
以下三个示例展示了营销公司的供应链安全可能面临风险的地方。
1) 无法获得关键原材料
大多数新型农用化学品 AI 合成的最后一步相对简单，涉及两个复杂中间体的偶联。这通常需要基本设备，并采用大多数制造商都可以操作的流程。通常更困难的部分是关键中间体的制造，这通常需要复杂的技术和专用设备。正是在这个阶段，营销公司的了解有限，结果暴露了供应链问题。
从有机化学的角度来看，情况并非总是如此。较早的 AI 涉及更简单的合成途径，并使用许多 AI 共有的中间体，这些中间体可从许多供应商处获得（参见图 1 中的三嗪示例，第 34 页）。
即将失去基本 AI 专利保护的新型 AI 需要更复杂的中间体，其中一些是制造特定 AI 所独有的。如果关键中间体的供应商因环境或健康与安全立法而失去其生产许可证，或者如果 AI 发明公司签订供应协议以购买关键中间体的全部产能，将会有什么后果？
表 2（第 38 页）显示了 Enigma Marketing 确定的三种 AI 失去了基本的 AI 专利保护并且需要没有其他农用化学品用途的中间体。希望在未来进入这些市场的营销公司需要确保这些关键中间体的安全供应。
2）工艺专利
一旦产品失去基本的专利保护，特别是当混合物专利等其他防御策略受到限制时，工艺专利可以成为关键的防御策略。这适用于氟虫腈； BASF 正在与多家公司进行诉讼（请访问我们的网站，了解有关氟虫腈专利侵权、工艺纠纷和作物生产技术的其他重要发展的每日新闻更新）。
现有多项氟虫腈及其中间体的工艺专利。许多，但不是全部，都分配给了巴斯夫。许多与氟虫腈复杂合成途径的最后一步有关。因此，从非巴斯夫来源购买氟虫腈 AI 的买家需要确保制造过程不侵犯巴斯夫的两项关键专利（见图 2）：
EP0668269 – “Process for the sulfinylation of heterocyclic compounds,” which expires in February 2015. EP0668269 involves the direct sulfinylation of the key intermediate shown in Diagram 2.
EP1222173 – “Process for preparing 4-trifluoromethylsulfinylpyrazole derivative,” which expires in October 2019. EP1222173 is an improvement of the oxidation step and generic manufacturers must therefore use different oxidation conditions to those described by this patent.
Marketing companies rarely have the in-house expertise to assess whether or not their supplier is infringing on process patents and must rely on the manufacturer of the AI to confirm that it is operating a legal process. However, this would not absolve the marketing company from litigation and damages should it be proven that the AI has been manufactured by a patent-protected process. In Enigma’s AgriBase database, 35 Chinese companies claim to manufacture fipronil. The question is: Do they have the capability to understand the complex process patent situation and manufacture fipronil without infringing BASF’s patents?
3. Lack of capability to test quality of product
甲基磺草酮制造中涉及的化学和技术相对简单，涉及一些可从多种来源获得的基本中间体。然而，在欧盟，甲基磺草酮生产过程中产生的杂质 1-cyano-6-methylsulfonyl)-7-nitro-9H-xanthen-9-one 被认为具有毒理学问题和浓度水平。它在技术产品中必须保持在 0.0002% (w/w) 以下。先正达已为甲基磺草酮的生产申请了多项工艺和纯化专利，包括：
EP1979310 (A1) which is to a process for the crystallization of mesotrione.
EP1377544 (A2) 是关于 2-硝基-4-甲基磺酰苯甲酸的纯化，它是甲基磺草酮制造中的关键中间体之一。
EP1786767 (A1) 涉及选择性控制甲基磺草酮的热力学稳定形式 (1) 或动力学稳定形式 (2) 多晶型物结晶的方法。
EP1740534（已授予专利，有效期为 2025 年 3 月）。降低甲基磺草酮中氰化物含量的方法。
EP1682497 (A1) 是一种降低甲基磺草酮中不良杂质水平的方法。
In Enigma’s AgriBase database, 17 Chinese companies claim to manufacture mesotrione. Again, the question is: Can they achieve the required specification for the European (and other) registration systems without infringing Syngenta’s patents?
Chinese manufacturers do offer two grades of mesotrione, one that does meet the above impurity level and one that doesn’t. A number of questions arise:
â– Why have two standards?
â– Can/do marketing companies check for this level of impurity?
â– Can/do registration authorities check for this level of impurity?
这是许多营销公司未能充分解决的供应链管理的关键问题。
原辅料的购买者需要引入更严格的供应链管理系统和审计系统，以特别注意中间体和原辅料的供应安全，并确保制造过程没有侵犯工艺专利。 AI 供应商需要有更透明的管理和制造系统，营销公司可以理解这些系统，以支持他们在注册和将仿制药推向市场方面所做的投资。
总而言之，供应商和采购商之间必须建立更密切的关系，因为在进入市场之前需要进行大量投资，而这必须以安全的供应链为基础。