What is an Active Pharmaceutical Ingredient?
“active pharmaceutical ingredient (API)
Any substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.”
This definition implies, for example, that commercially available premixes of APIs (such as the popular amoxicillin + clavulanic acid premix) can be regarded as an API, which is not correct. This definition thus may lead to misinterpretation.
What is an active ingredient? What is the difference between an active ingredient, an active pharmaceutical ingredient, and a bulk process intermediate?
Active ingredients are the substances in drugs that are responsible for the beneficial health effects experienced by consumers. The active ingredient in a pharmaceutical drug is called an active pharmaceutical ingredient (API). An example of an API is the acetaminophen contained in a pain relief tablet. The active ingredient in a biological drug is called a bulk process intermediate (BPI). An example of a BPI is the insulin contained in an insulin pen cartridge, for use by diabetics.
Why regulate active ingredients?
The quality of active ingredients in a drug has a direct effect on the safety and efficacy of that drug. Poorly manufactured and contaminated active ingredients have been associated with negative health outcomes, including death, in a number of incidents over the past decades. For this reason, most countries around the world are now regulating active ingredients.
Which requirements and guideline should I use for the manufacturing of an active pharmaceutical ingredient?
The ICH Q7 Guideline is a quality standard that governs the manufacturing of active ingredients. The ICH Q7 Guideline was established by an international organization known as the International Conference on Harmonization, which includes several countries, including the United States, Japan and the countries of the European Union.
Should GMP according to ICH Q7 be applied for manufacturing steps before the defined API starting material, i.e., steps not identified in grey in Table 1?
ICH Q7 does not apply to steps prior to the introduction of the API starting material. However, there is an expectation that an appropriate level of controls suitable for the production of the API starting material should be applied (ICH Q7, section I.C (1.3)). Normally, the API-starting material is defined in the regulatory filing by the applicant and approved in the regulatory reviewing process. Additional guidance is provided to define and justify API starting material derived from various sources (ICH Q11, section V (5)); for master cell banks, see ICH Q5B, ICH Q5D.
A general scheme of systems for auditing the manufacture of API consists of the following:
- Quality System assures overall compliance with CGMPs and internal procedures and specifications.
- Facilities and Equipment System includes activities which provide an appropriate physical environment and resources used in the production of APIs.
- Materials System includes measures and activities to control starting materials, intermediates, and containers. It includes validation of computerized and inventory control processes, storage, and distribution controls.
- Production System includes measures and activities to control the manufacture of APIs, including in-process sampling and testing, and process validation.
- Packaging and Labeling System includes measures and activities that control the packaging and labeling of intermediates and APIs.
- Laboratory Control System includes measures and activities related to laboratory procedures, testing, analytical methods development and methods validation or verification, and the stability program.