It is a fundamental expectation that manufacturers of drug substances validate their processes as appropriate. From an ICH
perspective, process validation is "the documented evidence that the process, operated within established parameters, can
perform effectively and reproducibly to produce a drug substance or intermediate meeting its predetermined specifications
and quality attributes" (1). The targeted result of process validation is the collection of scientific evidence to support
claims that a process is stable and capable of providing a predictable and repeatable output. Validation activities are expected
to be pursued from initial drug-substance design through to the processes employed for manufacturing, including packaging.
Employing the CTD format for information submission
Drug substance quality, safety, and efficacy data must be compiled and placed into the Common Technical Document (CTD) format.
Additional guidance pertaining to FDA's requirement for electronic submissions can be found in Guidance for Industry: Providing Regulatory Submissions In Electronic Format—Certain Human Pharmaceutical Product Applications
And Related Submissions Using the eCTD Specifications (11). According to ICH M4, the CTD is broken down into four modules (note: the first bulleted point is not part of the CTD):
- Module 1—Region-Specific Information
- Module 2—Quality and overall summary and clinical overview and summary
- Module 3—Quality
- Module 4—Nonclinical study reports
- Module 5—Clinical-study reports (12-16).
According to FDA's guidance, organization of the electronic submission should be in folders that align with Modules 2 through
ICH Q11 requires the manufacturers of drug substances to implement continuous-improvement practices throughout the entire
lifecycle of each drug substance. The employment of science and risk-based approaches for each lifecycle stage is a fundamental
expectation of the ICH Q11 Guidance Document (1). A true lifecycle will encompass all stages from initial design and development,
validation of processes, manufacturing, commercialization, and end-of-life. Manufacturers are expected to evaluate manufacturing
processes, the control strategy, and ongoing product safety and efficacy. All knowledge garnered during these evaluations,
including knowledge gained from post-market surveillance activities, should be used to drive ongoing product improvement.
Additionally, information collected should include:
- Process-development activities
- Technology-transfer activities
- Process-validation studies
- Change-management activities (1).