Orchestrating six systems


FDA compliance programs provide instructions to its inspectors to assess compliance of pharmaceutical activities with the Federal Food, Drug, and Cosmetic Act and other laws administered by the FDA. Compliance programs are available to the public under the Freedom of Information Act. They cover medicinal product activities in order to assess if they meet the requirements of regulatory provisions.


Indeed, according to section 501 (a) (2) (B) of the Act, an API can be adulterated for health reasons or if it contains impurities hazardous to health, or even can be considered falsified if it is not of the content, quality and purity expected to meet standards. The Act requires that all medicinal products be manufactured in compliance with good manufacturing practices (cGMP). No distinction is made ​​between an API and a medicinal product  and any compliance failure is a violation of the Act. An API manufacturer is considered to be operating in a state of control when it uses the conditions and practices that ensure compliance with Section 501 (a) (2) (B) of the Act.

Another non-compliance condition is a failure with the rules of good manufacturing practices for medicinal products (21 CFR Parts 210 and 211). The FDA recognizes that these rules apply without restriction to active pharmaceutical ingredients, starting with the raw materials and validation of critical process steps that affect the quality and purity of the final API.

For manufacturers, the means of control and monitoring must be commensurate with the index of risk prioritization and stricter when approaching the final product. The expected requirements are also detailed in the ICH Q7 which aims for APIs to meet the characteristics of quality and purity that they claim or that they are shown to possess.


To this end, the FDA has developed an approach to the process of inspection for pharmaceutical active substances regardless of their origins (7356.002F). The inspection boards are structured for efficient use of resources for routine monitoring of API manufacturing facilities, while recognizing that not all processes and systems will be covered as part of an inspection. Firstly, the system approach enables the assessment of their compliance one by one, while considering the inter-correlation of these systems. Secondly, this approach also makes it possible to periodically be more or less thorough, depending on the context of the inspection, allowing completeness. A so-called monitoring inspection will be conducted routinely but compliance inspections will be carried out in case of violation.


For the system approach, the FDA considers the manufacturer’s specific activities, history of inspection, and systems previously inspected in order to cover the entire life cycle of the API in a timely manner.

The description of each system or process covered allows the manufacturer to consider an approach of 6 systems at the service of the API. It is important to understand that the quality system covers 5 other systems related to manufacturing:

1. Materials

2. Buildings and equipment

3. Quality system

4. Packaging and labeling

5. Production

6. Control Laboratory


ICH Q7 Sections 3, Personnel, and 6, Documentation and Records, apply to all systems

Quality system

The evaluation of the quality system has two parts. The first concerns control of documents for intended use in connection with the expertise of its users. The second is related to other systems and focuses on quality indicators for problem management.

ICH Q7 reference sections:

• Section 2, Quality Management

• Section 13, Change Management

• Section 14, Refusal and reuse of materials

• Section 15, Complaints and recalls

• Section 16, Manufacturers under contract (including laboratories)

Buildings and equipment system

This system includes measures and activities that provide an appropriate environment and resources and equipment used in the manufacture of active pharmaceutical ingredients. It assesses staff training and compliance with procedures that result.

ICH Q7 reference sections:

• Section 4, Buildings and facilities

• Section 5, Manufacturing facilities

• Section 6, Documentation and records

Materials system

This system includes the control measures and activities of finished products and materials incorporated therein, and packaging materials, considering their supply, quality, sampling, status, labeling and storage in connection with staff training and appropriate documentation. It involves the validation of related electronic systems.

ICH Q7 reference sections:

• Section 7, Materials management

• Section 10, Storage and distribution

• Section 4.3, Water

• Section 6, Documentation and records

Production system

This system includes the control measures and activities of the manufacture of active pharmaceutical ingredients, through written and approved manufacturing processes and the assessment of their performance, change management, control of critical points and quality management that follows.

ICH Q7 reference sections:

• Section 6, Documentation and records

• Section 8, Production and in-process controls

• Section 12, Validation

• Section 18, Specific provisions for active substances produced by cell / fermentation culture

Packaging and labeling system

This system includes control measures and activities of packaging and labeling of active pharmaceutical ingredients. It includes written procedures, change management, use, storage and printing labels, and control of packaging and labeling operations. It involves the validation of these operations and related electronic systems.

ICH Q7 reference sections:

• Section 9, Packaging and identification labeling of active substances and intermediates

• Section 17, Agents, brokers, traders, distributors, repackagers and relabellers

Laboratory Control System

This system includes the control measures and activities related to staff, facilities, formalized methods and specifications, development, and validation or verification of analytical methods and stability study programs. It involves control of data and quality indicators related to these activities.

ICH Q7 reference sections:

• Section 11, Laboratory Controls

• Section 6, Documentation and Records

• Section 12, Validation