Chemistry Reference
In-Depth Information
spectrometer, which is well suited for glycopeptides due to its extended mass range.
Glycosylation is a posttranslational modification that plays a critical role in deter-
mining the efficacy and safety of a therapeutic protein. Glycosylation can be ana-
lyzed on the intact protein by mass spectrometry, as released glycans by a variety
of techniques, or as glycopeptides in LC/MS peptide maps. When glycosylation can
be characterized with LC/MS of the glycopeptides, the site of attachment can be
directly determined and structural information can be obtained through MS/MS
experiments. The example in Figure 7.13 shows that LC combined with ESI/TOF
(electrospray ionization/time-of-flight) mass spectrometry is a powerful tool for the
rigorous characterization of peaks in a peptide map.
7.7 cleAnIng metHod vAlIdAtIon
Cleaning validation is the process of assuring that effective procedures are used to
remove residue from pharmaceutical manufacturing equipment. The main rationale
for requiring clean equipment is to prevent contamination or adulteration of drug
products. A proper cleaning validation program provides documented proof that one
can consistently and effectively clean a system or piece of equipment.
The required use of clean equipment is not new. Good Manufacturing Practice
(GMP) regulations in place as early as 1963 stated that “equipment shall be main-
tained in a clean and orderly manner” [41]. In 1978, updated GMP regulations
included a similar section on equipment cleaning, which states that “equipment and
utensils shall be cleaned, maintained, and sanitized at appropriate intervals to pre-
vent malfunctions or contamination that would alter the safety, identity, strength,
quality, or purity of the drug product” [42]. More recently, the development of highly
active drug substances, commonly referred to as “potent compounds,” has placed
more emphasis on cleaning validation to address issues of containment, cleaning,
and decontamination [43]. This section briefly discusses cleaning validation and
relates it to various method validation approaches. Several references are available
on this subject and should be consulted for additional detail [45-49].
7.7.1 g
enerAl
r
eQuIrementS
In two recent publications, the FDA has outlined certain general requirements for
compliance with cleaning validation regulations [50,51]. Written general proce-
dures on how cleaning processes will be validated must be prepared. Sometimes
referred to as a cleaning validation master plan, this document should address
responsibilities, facilities, cleaning strategies, analytical strategies, residue limit
justifications, and change control procedures [52]. The cleaning validation proto-
col should describe the equipment to be cleaned, methods, materials, and extent
of cleaning, parameters to be monitored and controlled, and analytical methods.
The protocol should also indicate the collection and type of samples (boil-outs,
rinses, or swabs), and how they are labeled, stored, and transported to the labora-
tory for analysis.
During the cleaning validation process, various cleaning agents and the means
of measuring residues, and the means for determining drug-product-related residues
