Quality assurance for finished pharmaceuticals, biopharmaceuticals, medical devices, and active pharmaceutical ingredients (APIs) includes the specification and control of those components that have product contact during manufacturing, that is, the raw materials (RMs).1-6
GMP REQUIREMENTS GMP regulations and good business practices require that pharmaceutical RMs and their suppliers be qualified both initially and periodically.1-3,6,7 Similar requirements can be found in the US Code of Federal Regulations, ICH guidance documents, European GMP regulations, and within ISO.Patient safety is a key reason for this requirement, dating back to several unfortunate events within the pharmaceutical and food industries. In one incident, the use of an unsuitable RM led to widespread toxicity, resulting in hallucinations and other severe symptoms.8 Mix-ups and errors of identity have also occurred. For example, the accidental use of ethylene glycol instead of propylene glycol resulted in morbidity and mortality.
Regulatory requirements in the pharmaceutical industry have evolved over time to reduce the probability, or risk, of such events. Some of the most important actions a firm takes to reduce risk include setting specifications that define and control the RMs, testing to verify identity and quality, and establishing systems to prevent the use of unsuitable materials.3
RM qualification should be carefully defined in GMP procedures and placed under strict change control. Both the chemical entity and suppliers must be qualified, usually in tandem. RMs deemed "critical" require testing of more supplier lots for more attributes and extensive supplier evaluation before qualification is achieved. The critical status of an RM is related directly to its intended use in the process and to the potential risk created by a quality deficit in the RM that may adversely impact the product's identity, purity, potency, toxicity, or efficacy.11,12 An RM may be critical to one process but not to another. Each firm must identify which materials are critical and justify the choices made and the additional oversight required.
Table 1 summarizes the applicable regulations for pharmaceutical products of various types, and summarizes some of the differences between US and European regulations. These differences may create complex challenges for the firm that manufactures multiple profile classes of products for worldwide sale. Considering the rapid rate of change to these regulations, sustaining a compliant, effective program requires a strategic approach.
Business needs. In establishing an RM qualification program, first determine your internal business requirements. A development organization will usually need a rapid, flexible RM qualification process that can quickly assess up to 100 or more new materials and suppliers and approve them for at least provisional use. Furthermore, changes in RMs and suppliers are expected during development.5,6 Therefore, full qualification of an RM may proceed in parallel with its use and should be completed at a defined project milestone.
System procedures. In order to qualify new RMs from new or existing suppliers, several GMP procedures and systems are needed (see Table 2). In writing these procedures, consider compliance as well as efficiency. Check that the different documents link with each other appropriately and do not contradict each other. Avoid the extremes of lumping many procedures into one document or splitting integrated procedures into different documents. Check that the procedures are clearly written and can be consulted and followed while on the floor.
A master plan is an invaluable document for both new and existing programs. This document may be "live" (subject to periodic revision) or static (created at one moment in time). Some firms archive master plans within a quality manual, while others place the information within a standard operating procedure.2