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
An RM qualification and control program is considered a key factor in assuring the quality of medicinal drugs, yet it is often
deemed of secondary importance at a busy firm. Usually, RM testing is not considered scientifically challenging or exciting
- until, of course, the supply chain is imperiled by a single failure. At this point, a great deal of scientific and compliance
information must be quickly sifted through and presented to an investigation team, then both short-term and long-term actions
initiated. The data are often not readily accessible or transparent and require the collaboration of subject matter experts
to integrate and interpret.
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.
Legally, a pharmaceutical firm takes on full responsibility for the quality of the RMs it purchases and uses in a cGMP manufacturing
process. Consequently, it is in the business interest of a firm to exercise reasonable oversight of suppliers and test laboratories
and to characterize RMs appropriately.9,10
Table 1. References to regulatory requirements
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.
A firm faces the practical challenge of establishing and operating an efficient, compliant system that assures continuous
supply of quality RMs that are sampled, tested, and then released for manufacturing needs on time. A properly sized and managed
warehouse provides a buffer zone where unpredictable RM problems (back orders, late deliveries, and items failing to meet
specifications) can be resolved without delaying manufacturing. However, it is undesirable to build large warehouses and store
huge inventories if materials must be discarded because they expire before use. Therefore, it is important for supply chain
management to reduce the probability of receiving RMs that fail to meet specifications. This is part of the payoff of a robust
and sustainable vendor and RM qualification program.7,9,10
Table 2. List of procedures needed for RM qualification program
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
In contrast, an organization with a mature, marketed product is unlikely to have frequent changes in RMs, and long-term supplier
relationships are commonly in place. Any changes may require overcoming regulatory hurdles and are highly undesirable. Consequently,
all RMs are likely to be fully qualified before use and the quality program will focus on maintenance and monitoring of the
Table 3. Master plan items
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