5.0 COMMERCIAL MANUFACTURE
5.1 Equipment Vessels
equipment such as compounding vessels, holding tanks or high/low shear mixers
are designed for pharmaceutical use. 21 CFR 211.63 states that
‘Equipment used in manufacture, processing or packing or holding of a drug
product shall be of appropriate design, adequate size and suitably located to
facilitate operations for its intended use and for its cleaning and maintenance’
Materials of construction for
equipment will have considered ease of cleaning and should not react to active
materials or excipients used in manufacturing, performance during sterilisation
and quality of finish is also considered.
Product contact surfaces must be smooth and continuous with minimum
welds, polished internally and inhibitive for microbial proliferation. Stainless steel 316L is the preferred choice
within the pharmaceutical industry and is used to construct equipment in direct
contact with pharmaceutical products including water system tanks and pipelines
while 304 is used for non-contact applications.
Stainless steel 316L has better overall corrosion resistant properties regarding
pitting and corrosion within chloride environments and is stronger at elevated
temperatures. However, ‘rouge’ is the commonly used term for
the visible corrosion of stainless steel.
Rouging is typically found in water generation systems, manufacturing
vessels and pipework that are routinely exposed to corrosive solutions. Rouge on a product contact surface can create
a surface that is difficult to clean and sanitise allowing an environment for
microbes to thrive. It should be
considered whether preventative maintenance in which treatment to prevent
potential rouge from happening or corrective maintenance to correct the problem
once it has occurred should be used. Risk
assessments should be completed to evaluate potential impact to product,
patient, personnel and equipment. Chlorine containing compounds should not be
used when cleaning manufacturing vessels, pipework or equipment manufactured
from 316L or 304 stainless steel. All
equipment should be stored in a manner where microbial ingress or proliferation
can be prevented. Replacement parts
should be replaced with identical parts which demonstrate the same performance
as shown during system validation.
‘Operations shall be performed within
specifically defined areas of adequate size.
There shall be separate or defined areas or such other control systems
for the firm’s operations as are necessary to prevent contamination or mix up’.21 CFR 211.42(c). * The clean room is
used to minimize the introduction, generation and retention of particles inside
the room. During the design of the clean
room consideration is given to strict guidelines, creating the need for high
specification clean rooms that meet all regulations as defined in Annex 1 of
the EU Guidelines to Good Manufacturing Practice and PIC/S (Pharmaceutical
Inspection Co-operation Scheme) GMPs. Relevant
parameters such as temperature, humidity and pressure are controlled as
necessary. The potential for skin
particles and other material carrying microorganisms to contaminate product can
be reduced by effective ventilation.