Chemistry Reference
In-Depth Information
tAble 7.8
potential sources of contamination targeted during cleaning validation
• Active ingredients
• Synthesis precursors/starting materials
• Reaction by-products
• Degradation products
• Excipients
• Organic solvents
• Microbes (
E. coli
)
• Endotoxins
• Cleaning agents (solvents, surfactants)
• Buffers
• Media
• Lubricants
• Particulates
• Filtering agents
• Residual rinse water
• Environmental dust
• Wear products from equipment
are evaluated. A list of potential contaminants, etc., is provided in Table 7.8. To
monitor drug product residues, companies generally test for the active ingredient.
Endotoxin testing may also be performed. Measuring the residue of cleaning solu-
tions can be problematic because they can contain more than one active component.
One can either develop a test for the most abundant component or use a whole-product
approach. In the whole-product approach, a determination is made as to whether any
residue is present, without regard for its origin. A standard whole-product approach
assay is commonly performed by measuring Total Organic Carbon (TOC), which
can detect virtually every product and cleaning agent residue. HPLC is another com-
monly used technique.
7.7.2 e
QuIPment
c
leAnIng
Another important consideration is evaluating how cleaning is best performed.
Equipment can be cleaned by various procedures: Clean in Place (CIP), Clean out of
Place (COP), and manual cleaning can all be utilized. CIP is performed by circulat-
ing cleaning solutions through the equipment. Cleaning solutions can be recirculated
or immediately drained. When practical, or necessary, CIP systems should be disas-
sembled during cleaning validation to facilitate inspection and sampling of inner
surfaces for residues or contamination. For COP, whether manual or automated,
equipment is removed and cleaned remotely. Although pharmaceutical companies
generally prefer automated approaches, human intervention for manual cleaning is
still necessary in some instances. Obviously, any time manual cleaning is imple-
mented, personal hygiene must be taken into account.
