It is important to qualify the contractor before signing a contract with that firm. Otherwise, the ability to help the contractor become more FDA compliant or choosing another contractor is impaired by a signed contract before audit.

Manufacturing operations. The manufactured product and process should be defined, from design to delivery. Control must be exercised over all changes. Documenting processes, associated controls, and changes to processes will ensure that sources of variability are identified. Documentation should include:

• Resources and facilities used
• Procedures to carry out the process
• Process owner who maintains and updates process as needed
• Identification and control of important variables
• Quality control measures, necessary data collection, monitoring, and appropriate controls for product and process
• Validation activities, including operating ranges and acceptance criteria
• Effects on related process, functions or personnel.

From a regulatory perspective, it is important to have experts in a pharmaceutical environment who understand pharmaceutical science, equipment, facilities, and process types and how variations in materials and processes can ultimately affect the finished product.

All inputs (i.e., materials, purchased or manufactured, that go into a final product) to the manufacturing operations must be examined. Materials are components, containers, or closures. Quality systems should ensure quality controls are established prior to the receipt, production, storage and use of all inputs. Suppliers of input materials must be audited on a periodic basis. An essential element of purchasing controls is the data trending for acceptance and rejection of materials for information on supplier performance. The auditing of suppliers should be based on a risk assessment. An audit should determine the reliability of a supplier's certificate of analysis (COA). A quality-system approach ensures the procedures are established to verify that materials are from qualified sources. Equally important is to have a system in place to respond to changes in materials from suppliers to avoid unintended consequences.

Design concepts established during product development typically matures into commercial design after process experimentation and progressive modification where areas of weakness are identified, corrected, and monitored. Critical quality attributes should receive increased scrutiny. Risk management should help identify areas of process weakness or higher risk and factors that may influence critical quality attributes.

A robust manufacturing process should be in place before commercial production. FDA recommends that scale-up studies be used to help demonstrate that a fundamentally sound design has been fully realized. Proper design and reliable technology transfer processes should ensure the ability to validate the manufacturing process. Validation provides initial proof the design produces intended product quality. Validation is not a one-time event.

The quality-system approach calls for manufacturers to develop procedures that monitor, measure, and analyze the operations, including analytical methods and statistical techniques. The quality-system approach indicators that change control is warranted when data analysis or information reveals an area needing improvement. Changes must be controlled and documented. In other words, the entire product life cycle should be addressed by the establishment of continual improvement mechanisms in the quality system.

Under a quality system, there will be a process in place to handle nonconforming material and product so that it is not placed into distribution. This process must be documented and must define responsibilities for halting and resuming operations, investigating discrepancies, recording nonconformity, and taking remedial action. Investigation, conclusion, and follow-up of nonconformities or deviations must be documented. Remedial action may include correction of the nonconformity, thereby allowing the product to proceed with proper authorization and justification of the conclusion regarding the problem's impact and use of the product for another application where the deficiency does not affect the products' quality or reject the product.

Evaluation activities. It is important to analyze manufacturing data on a regular time interval for trends as a means to control the operation. This analysis will detect potential problems early and enable the planning of corrective and preventive actions.