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1 Introduction and Historical Development
INTRODUCTION
Dale A. Seiberling
Electrol Specialties Company (ESC), South Beloit, Illinois, U.S.A.
Many technical reference books begin with areview of the development of the
subject material. Your editor, and the author of this chapter, has followed that
practice in many prior publications. However,clean-in-place (CIP) did not start and
was not initially developed in the pharmaceutical or biotechnology industries. It
began morethan 55 years ago, on the dairy farm, as the means of cleaning the newly
introduced Pyrex w (Corning Incorporated, Corning, New York) glass milking
system pipelines. During the subsequent 15 years, it was adopted by the dairy,
beverage, brewery, winery, and food processing users. Only during the past two
decades, has CIP been widely adopted by the biopharmaceutical industries.
My recent teaching experience has suggested that the technical personnel of
the industries to which this book is directed are more interested in the current
CIP technology than its historical development and application. Therefore, clean-inplace
for biopharma ceutical processes will start with aquestion, “What is CIP?” in the
biopharmaceutical industry at this time? A generic two-tank process and
transfer line will be discussed in depth to provide the reader with an overview of
the technology and some direction to those chapters in which the full detail can
be found.
But first, it is necessary to consider the broad subject of “cleaning.” Batch
manufacturing processes require cleaning as one of many manufacturing steps.
Whereas cleaning has long been recognized to be an important procedure, until
recent years it was performed manually,typically by the least experienced and least
trained employees under little, if any, supervision. The equipment and supplies
provided to accomplish cleaning were also, in many cases, substandard. Cleaning
in the biopharmaceutical process, however,isasimportant as the production of the
active ingredients,the formulation and filling of those ingredients,and the sterilizein-place
(SIP) of the process equipment. Effective cleaning is the most important
precedent to SIP as sanitization/sterilization requires contact between steam and
microorganisms that will not achieve the desired time-temperature conditions if
product residue insulates and/or protects the microorganisms. And it is well
understood that chemical residue contaminants must be removed aswell. It is
also well understood that sterile filth in apharmaceutical product is no more
desirable than unsterile filth.
Cleaning can be accomplished by disassembly of the equipment followed by
manually washing and rinsing, or transfer of the parts to acleaned-out-of-place
(COP) system. Or,itcan be accomplished “in-place,” by the CIP procedure. Tunner
(1),when writing about validation of manual cleaning, states, “The most important
difference between manual and automated cleaning can be summarized as the
human factor, with the inherent variability of personal training and commitment
to quality.” He cites DeBlanc and coworkers’ (2) observation that “cleaning is not
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