Setting Comprehensive Specifications in API Manufacturing


Developing specifications (specs) for the manufacture of New Chemical Entities (NCEs) or Active Pharmaceutical Ingredients (APIs) requires a comprehensive and critical analysis of the requirements that are used in developing and validating sound analytical methods.

Learn how to accelerate your API manufacturing project »

The approach to setting specifications has undergone significant change, due to new international ICH Guidelines. Because of this, it’s important for CMOs and their sponsors to have a process-driven approach to specifications development in order to meet both FDA and ICH standards.

At each stage of development – from Phase 1 through to securing FDA approval, companies need to ask themselves what is absolutely necessary to successfully commercialize the NCE and ensure safety and efficacy.

These specifications enable you to lay out what you hope to accomplish and how it meets a generally accepted standard. While it’s not always possible to meet those guidelines because of the very nature of API’s once you have a thorough understanding of what’s required.

So really, a process specification is a test for assay and/or impurities, residual solvents, etc. and where they may have come from – whether that is from the process or raw materials.

Those specifications are submitted to the FDA by the sponsoring company and not only inform the FDA of the validity, efficacy and safety of your proposed chemistry, but they also provide a blueprint of sorts for the development of future batches of the API.

Specifications Require a Cross-Functional Group

Since specifications are critical quality standards proposed and justified by the CMO working alongside the sponsoring company and approved by regulatory authorities, it’s important to achieve a consistent approach to setting them, and having a cross-functional group including quality, development, toxicology, and regulatory review who work together to develop them.

Do you have questions about your API Manufacturing Project?

Let us know. We can help.

In the early phases of clinical development, the specifications should be based on the results of toxicology studies that provide purity limits. As development advances with clinical studies, the specifications should evolve to encompass tighter acceptance limits based on manufacturing capability and stability data. Once submitted to the FDA, the specifications may need to be revised and would require a new round of review and approval of the revised specifications by the internal quality, analytical development, process development, toxicology and regulatory functions.

For this reason, it’s important to keep lines of communication and collaboration open among the functional groups through every step of the process.

Analytical Methods Key to Sound Specifications

The analytical methods used throughout a specific project should be appropriately validated using ICH Validation of Analytical Procedures. The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. Documentation of analytical methods forms a key part of the specifications.

Pharmaceutical manufacturing continues to evolve with advanced technology, tools and processes for sound analytical methods and testing. Effective use of the most current pharmaceutical principles and knowledge which is documented in specifications that are carried throughout the life cycle of a chemical, can lead to faster commercialization, as well as safe and effective products.

For more on ICH guidelines, check out “API Quality Risk Management,” “Understanding what stage of API development you should start to think about ICH guidelines” and “Despite all the Rhetoric, Time-Consuming FDA Guidelines Make More Work for CMOs but Safe Products for Consumers.” To ask us questions, call us at (978) 462-5555 or email us at