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I
n 1988, the Parenteral Drug Association confirm the earlier statement that human-
(PDA) published a position paper on borne contamination is the most critical
aseptic processing in response to intense risk factor in aseptic processing. Numer-
interest in aseptic processing in the in- ous industry surveys and technical arti-
dustry at that time and in partial response cles published since that time are in ac-
to the publication of the Food and Drug cordance with this statement. (3–8).
Administration’s (FDA’s) 1987 guideline Since the publication of the 1987 guid-
on aseptic processing (1, 2). The intent of ance, firms have continued to implement
DIGITAL VISION
this review is similar to that of its 1988 new technologies and aseptic processing
predecessor: to identify and discuss the improvements to better control human-
current capabilities of aseptic processing borne contamination. At the same time,
technology. the industry has implemented expanded
This article reviews current The improvements to aseptic process- microbial-test regimens and more com-
industry practices and ing operations described in the 1988 po- prehensive process simulation testing to
sition paper were characterized in the ensure that aseptic processing systems
regulatory expectations for the
opening section of that document as “evo- have adequate process capability and that
aseptic processing of sterile lutionary.” The improvements in aseptic this capability is consistent and as repro-
drugs. It provides comparisons processing technology that have occurred ducible as possible within the technical
and outlines points of tension since 1988 would perhaps be better char- constraints that are inherent in the meas-
between curent manufacturing acterized as “revolutionary.” We believe urement of aseptic performance.
technology and capabilities with that the practices described in 1988 are, This article describes the improvements
by and large, as valid now as they were in conventional and new technologies that
regulatory “requirements” for
then. We also believe that products man- have occurred since the late 1980s. It also
this important activity. ufactured in compliance with the under- describes the improvements that have
lying principles outlined in the 1988 doc- been made in aseptic process validation
ument are still inherently safe. and control. Finally, the paper discusses
The aseptic manufacture of sterile prod- the technical limitations that still exist in
ucts is perhaps the most difficult challenge the evaluation of aseptic processing and
faced within the healthcare industry. Asep- raises concerns regarding the increasing
tic processing requires the careful appli- regulatory tendency to ignore the exis-
James Agalloco is the cation of microbiological contamination tence of those limitations.
president of Agalloco & control principles to exclude infectious
Associates, PO Box 899, Belle organisms from sterile products. We reaf- The condition of asepsis
Mead, NJ 08502. James firm our belief stated in 1988 that, “the Since the earliest days of parenteral man-
Akers, PhD, is the president
of Akers Kennedy & Associates.
major variable in the control of aseptic ufacturing it has been recognized that
Russell Madsen is processing arises not from the steriliza- many drugs and biologics would not with-
president of The Williamsburg tion processes, the cleanroom, or the fil- stand a physical sterilization process in
Group, LLC. tration processes that are so often the sub- their final container. Currently, a majority
*To whom all correspondence ject of technical papers and regulatory of parenterals and other products labeled
should be addressed. guidelines, but rather from the workforce sterile are manufactured using aseptic pro-
itself ” (1). Industry findings since 1988 cessing (8). It is therefore appropriate to
126 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
seems to us that in the past most indus- PDA’s Technical Report No. 22—suggest
Table I: Rank-ordered sources of try scientists and the regulatory commu- that zero contamination is an appropri-
microbial contamination in aseptic nity clearly understood that absolute steril- ate target (6, 11, 12). We believe it essen-
processing (3, 8). ity in aseptic processing was not possible tial to recognize the validity of zero as a
1986 2001 and therefore did not reflect a reasonable target but at the same time remind indus-
Personnel contaminants 1 1 expectation of outcome. It is now our be- try and the regulatory community that
Human error 2 2 lief that this appreciation is no longer as this target may not be consistently and
Nonroutine activity 3 4 widespread as it once was. uniformly attainable because no aseptic
Aseptic assembly 4 3 In the past, the perspective of process environment or aseptically produced
Mechanical failure 5 5 capability for aseptic processing, and hence product is provably sterile.
Improper sanitization 6 7 the requirements for process control, were
Material transfers 6 8 more solidly grounded scientifically. As The industry’s approach to
Surface contaminants 7 7 Block points out, there are pitfalls in using validation of aseptic manufacturing
Airborne contaminants 7 6 the word sterile in an absolute manner in In no other segment of the pharmaceuti-
Routine APAactivity 7 7 practical applications (9). For example, cal industry is the control of manufactur-
Failure of 0.2 filter 8 8 we have long understood that process fil- ing processes as critical as in the produc-
Failure of HEPA 9 8 ters that produced safe product could not tion of aseptically produced products. The
Improper sterilization 10 9 be demonstrated to yield sterile product recognition of the criticality of these
Other 10 in the “absolute” meaning of that word processes has led to the continued devel-
(10). In other words, we can always iden- opment of advanced production and qual-
review the concepts of asepsis and steril- tify organisms that could penetrate any ity assurance systems. Firms have contin-
ity before embarking on a discussion of filter that is practical for use in aseptic pro- ued to develop and implement more
key process requirements and validation cessing. Absolutism is dangerous even in rigorous methods for the validation of
principles for aseptic processing to clarify physical sterilization because it presumes aseptic processes (13).
some of the misconceptions that have crept that we can have discovered every exist- The resource and staffing requirements
into industry and regulatory belief over ing form of microbial life. for validation programs within the indus-
the years. A vital element in process design When we use the word sterile—whether try have continued to increase during the
and validation is a definition of the end- on a label or in a guidance document, past decade and a half. These increased
point. And it is not possible to establish an standard, or regulation in the pharma- validation efforts are comprehensive, in-
end-point and associated process control ceutical industry—we must consider that cluding both prospective validation and
parameters without careful consideration the meaning of the word cannot be taken ongoing validation maintenance. The
of the target and the capability of the in a literal, absolute manner because management of a sound validation pro-
process. doing so does nothing but ensure failure. gram requires the participation of special-
We believe that industry and regulatory While suggesting the acceptance of par- ists from various academic backgrounds
communities currently find themselves tial or incomplete sterility may be an in technical and administrative disciplines.
caught on the horns of a dilemma regard- anathema to those conditioned to think Validation costs across the industry have
ing aseptic processing. The dilemma arises that parenteral manufacturing must be certainly increased, and as might be ex-
directly from the seemingly logical but sci- microbiologically perfect, it is our view pected the most costly of all operations to
entifically flawed notion that it is possible that only by consideration of asepsis in a maintain in a validated state is aseptic
to prove that each and every lot of asep- careful, scientific manner can we avoid manufacturing. Only part of the increased
tically manufactured product contains unreasonable standards and correspond- costs can be attributed to the increased
only “sterile” material. Sterile is, if taken ingly impractical regulatory enforcement. technical complexity of aseptic operations.
in its most absolute meaning, a word that It is important to ensure that we as an in- Substantial portions of the increased costs
offers no room for uncertainty in meas- dustry are not trapped by semantics or are a direct result of increased regulatory
urement or outcome. Sterile means free of impossible-to-achieve standards borne of expectations. The following sections of
any viable organisms (6). This condition, misunderstanding. this article present examples of the types
however, is not now and never has been Perhaps industry chose poorly by label- of programs that make up the aseptic pro-
possible to prove in aseptic processing. ing aseptically manufactured products as cessing validation effort.
This dilemma is not new—it has been “sterile.” Little if any harm has come from Sterilization validation and qualification of
recognized for decades and should never this choice, however. In fact, it can be ar- sterilizers. Comprehensive engineering
have left our collective understanding. gued that the standards currently in place qualifications are conducted on each new
What has changed since the publication in industry clearly recognize the seman- sterilizer to ensure that the design and
of PDA’s 1988 position paper is an under- tic tension between sterile and aseptic. No functional specifications are met. These
standing of the inherent limitations of any current standard calls for zero contami- qualification activities are used as the basis
technology built around the exclusion of nation in media-fill process simulation for formalized change control programs
microorganisms rather than the physical tests or in environmental monitoring, al- that support the continued appropriate-
destruction of those microorganisms. It though several documents—including ness of the sterilizer over time. In addi-
128 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
nel the major source of contamination,
Table II: Media-fill survey comparison—acceptance criteria (19). their actions serve to distribute the organ-
Criteria 1980 1986 1992 1996 2001 isms within the environment. In PDA sur-
,0.05% 3 11.5% 7 13.2% 4 7.5% 6 12.5% veys on aseptic processing conducted in
0.05–0.09 2 7.7% 5 9.4% 12 22.6% 9 18.8% 1986 and again in 2001, industry opinions
0.10% 4 25.0% 19 73.1% 36 67.9% 51 92.6% 33 68.8% regarding the sources of contamination
0.11–0.20% 4 25.0% 1 3.8% 1 1.9% in aseptic processing were virtually un-
0.21–0.30% 3 18.8% 1 3.8% 5 9.4% changed (see Table I). Table I also shows
.0.30% 5 31.2% that the seven most prevalent sources of
contamination—identified as most likely
tion, the maintenance procedures and cal- ing responsibilities for sterilization to contribute microbial contamination
ibration requirements for all process con- processes are far more clearly delineated during an aseptic process—all are related
trol devices are developed, as are the nec- than they were in 1988. to activities performed by operators and
essary standard operating procedures for We are also concerned about the in- are virtually unchanged in relevance dur-
these activities. creasingly common practice of repeating ing the 15 years between these surveys.
Following completion of the qualifica- validation studies on a more or less an- We also have seen shifts in the technolo-
tion of the sterilizer, process validation is nual basis. There is no reason to believe gies applied for the sterilization of com-
undertaken to ensure that the sterilization that a sterilizer operating within validated ponents. Since 1988, environmental and
process complies with regulatory require- parameters for physical operation should occupational safety concerns have greatly
ments. These studies are designed to en- require periodic biological challenge test- reduced the utilization of ethylene oxide
sure that the conditions achieved through- ing. Modern steam and dry-heat steriliza- (EtO) for the sterilization of plastics and
out each sterilizer load result in the tion equipment is robust and reliable. other non–heat stable components. Of
delivery of the appropriate lethality for the There is no scientifically valid reason to course, EtO is still used and is still an ex-
process. Equally important, manufactur- repeat biological challenges when the tremely efficacious gas sterilant.
ing and quality assurance controls are de- process control and engineering data in- However, several other technologies
signed to demonstrate that the sterilizer dicate that the sterilization parameters and with similar levels of sterilization efficacy
operates reliability and reproducibly under equipment function are consistently have been introduced or have expanded
intended-use conditions during its oper- within target values. The imposition of in their use. Both gamma and beta (elec-
ational life. Validation typically includes unnecessary validation or revalidation re- tron beam) sterilization were used in 1988,
an adequate margin of safety to allow for quirements based upon unreasonable fear but they are more widely used today.
process variation. rather than scientifically meaningful analy- Lower-energy radiation technologies are
After the prospective validation has sis results in wasted resources and reduced coming into increasing use in sterilization
been completed, change control systems productivity, with no benefit to end users. of heat-labile materials. Also, new gas- or
are established to ensure that sterilizers Validation of sterilization procedures for vapor-sterilization methods have been in-
are maintained in a state of control. PDA components, containers, and closures that troduced. These include vapor phase hy-
commented in the 1988 position paper enter the aseptic processing areas. In 1988, drogen peroxide and chlorine dioxide.
that “revalidation” studies that are essen- PDA asserted that the sterility assurance In some respects, the methods used for
tially repeats of prospective validation level (SAL) of aseptically produced prod- component sterilization in the manufac-
studies on a periodic basis are not neces- ucts was “generally considered to be 103 ture of glass and elastomeric stopper con-
sary. Unfortunately, PDA’s position in this or more,” while physical sterilization tech- tainer systems have changed little since
matter has not gained the broad accept- nologies used in component preparation 1988. Moist-heat sterilization continues
ance it deserves. resulted in an SAL of “at least 106.” (It to be the most widely used sterilization
In addition to periodic performance should be noted that PDA correctly pre- method, and validation technology and
checks, calibration, and maintenance sented the SAL value as a positive expo- efficacy have changed little since 1988.
checks, firms enforce rigorous programs nent, not to be confused with the proba- Validated moist-heat sterilization
to ensure that no change is made to any bility of nonsterility concept use to assess processes continue to result in an ex-
aspect of the sterilization process or ster- risk associated physical sterilization meth- tremely safe outcome.
ilization equipment without a full inter- ods, which is a fraction of one and there- Dry-heat depyrogenation continues to
disciplinary evaluation. These change con- fore carries a negative exponent.) We be- be the method of choice for the steriliza-
trol programs are now far broader in scope lieve that the sterilization of components tion and depyrogenation of glassware. In-
and much more connected to the regula- is a very minor risk factor in aseptic pro- dustry develops and validates depyrogena-
tory function within firms than they were cessing, just as it was in 1988. tion processes to yield at least a three-log
in 1988. In the United States, firms follow The predominant cause of contamina- reduction of reference-standard bacterial
regulations that define requirements re- tion in aseptic processing remains the endotoxin. The resistance of endotoxin to
porting process changes to FDA. Similar same as it was in 1988: activities per- heat is at least an order of magnitude
practices are required outside the United formed by personnel in direct support of greater than even the most resistant spore,
States (12). Regulations defining report- the aseptic process. Not only are person- therefore a three-log or more reduction
130 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
in endotoxin results in a very low proba- ing manufacturing. In 1988, supplying tion without the need for human interven-
bility of nonsterility, far lower in fact that components was largely a manual process. tion to supply the filling machine is stan-
1026 (SAL . 106). The widespread adoption of continuous dard practice in all but the lowest through-
The most significant process risks asso- washing and depyrogenation of glassware put operations. The incremental
ciated with component handling have al- using “tunnel” systems began in the late improvements in operational efficiency of
ways been the aseptic handling required 1970s and was well underway in 1988. At the continuous glassware-processing sys-
in the initial setup of component supply that time, many aseptic filling operations tems have led to higher levels of through-
systems such as parts hoppers and feed required operators to supply the filling line put, while human interventions for main-
chutes poststerilization and in keeping with depyrogenated glass. Today, contin- tenance, correction of jams, or removal of
aseptic processing operations supplied dur- uous glassware washing and depyrogena- fallen containers have been reduced or in
some cases essentially eliminated.
Similarly, a great deal of engineering ef-
fort has been invested in developing stop-
per processing systems that minimize
human intervention. Continuous stopper
processors with continuous automated
supply have been introduced. Also, in
batch component feed operations, ad-
vanced aseptic technologies such as re-
stricted accesses barriers (RABS) or isola-
tors equipped with rapid transfer port
(RTP) technologies have all but eliminated
the risk of human-borne contamination.
Of course, many aseptic processing op-
erations continue to rely on human oper-
ators to supply components using aseptic
techniques. Some significant improve-
ments have been made in cleanroom
clothing during the past decade and a half.
These improvements have led to safer
human-scale cleanroom operations. The
filtration properties of cleanroom cloth-
ing have improved, for example, and new
hood, goggle, and face-mask systems have
resulted in less skin exposure, better seal-
ing, and improved operator comfort.
The 1988 PDA paper clearly stated “The
threat of contamination in aseptic pro-
cessing arises not from the sterilization
processes, the cleanroom, or the filtration
processes which are so often the subject
of technical papers and regulatory guide-
lines, but rather from the workforce itself”
(1). As a consequence, equipment suppli-
ers, cleanroom suppliers, and the pharma-
ceutical industry itself have reacted to this
challenge, systematically reducing the risk
of contamination. The continued imple-
mentation of automation and advanced
aseptic processing technologies will con-
tinue to incrementally reduce risks asso-
ciated with human-borne contamination
in aseptic processing.
Process filter validation. The basic prin-
ciples involved in product filtration are
generally the same today as they were in
1988 (15). Firms continue to carefully as-
132 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
sess fluid bioburden and use these data to Of course, there have been improve- errors in assembly
reaffirm the appropriateness of their fil- ments made in filter technology and in its • improved vent and gas filters with
tration systems. Firms generally reassess process control since 1988, including greater strength and reliability
bioburden on a periodic basis and clearly • improved materials of construction • increased usage of reliable sterilize-
define hold times and the temperatures of filter cartridges that have allowed in-place technology on both vent and
of materials that reduce the opportunity for greater use of in situ sterilization process filters, which further reduce
for microbial survival. The highly special- • using preassembled cartridge filters aseptic connections and manipula-
ized nature of filter validation generally rather than manually assembled fil- tions
requires considerable participation by fil- ter disk sets throughout the industry, • improved automated systems for in
ter vendors. thereby reducing the opportunity for situ evaluation of filter integrity.
Process simulation testing. It is our belief
that PDA’s 1996 technical report that fo-
cused on the validation of aseptic process-
ing is still the most comprehensive trea-
tise on process simulation or media-fill
testing of aseptically manufactured prod-
ucts (6). The reader is referred to that doc-
ument for detailed guidance regarding the
design of media-fill tests and the interpre-
tation of results.
Much of what was described as stan-
dard industry practice in the 1988 posi-
tion paper is still suitable today. Evolving
regulatory doctrine for media-fill test re-
quirements has become increasingly bur-
densome. Unfortunately, however, this has
not increased end-user safety. Particular
concerns include media-fill container re-
jection issues, length of fill and number
of units filled, personnel qualification, and
revalidation practices (16).
During the past few years, FDA has ap-
plied considerable pressure regarding the
rejection of units from the media-fill pop-
ulation that is incubated and inspected.
FDA’s concern in this regard is under-
standable: The media fill should not be bi-
ased by the removal of containers a firm
believes might have been compromised,
therefore yielding an unwelcome result.
The media-fill test must always be a sci-
entifically valid evaluation of the aseptic
process, and, as such, there can be no room
for artificial biasing of the outcome to-
ward success.
On the other hand, it is unreasonable
for regulators to hold that all media-filled
units—particularly those that would be re-
jected because they lack container/closure
integrity—should be incubated even as a
separate population. Incubation of con-
tainers that normally would be rejected for
lack of container/closure integrity accom-
plishes nothing. We agree that units should
not be rejected from the media-fill test
population for cosmetic defects only, even
if they would normally be rejected in prod-
134 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
uct manufacturing. comparable size. On the other hand, it is have increased since the introduction of
It is our opinion that far too much has equally clear that they should not be ex- higher throughput aseptic processing fill-
been made of this issue. It is possible to pected to be consistently lower either. The ing systems. In operations with fill speeds
ascertain whether a media fill is represen- alignment of intervention practices for at least 200 units/min, the duration of a
tative in terms of rejects by simply com- production and media fills should ensure media fill in which the target population
paring the normal lot rejection rate for this consistency of performance. was only 3000 would result in a media fill
container/closure integrity with that of In 1988 the number of units incubated that might last substantially less than 30
the media-fill test. It is clear that the re- by most firms in a media-fill test was al- min—not including set up. However, re-
ject rate should not be higher in media most always 3000 or slightly more. The quiring media-fill tests that are a high per-
fills than in normal production runs of number of media-filled units since 1988 centage of the total number of units filled
in a batch is not necessary to assess
process capability. Media-fill populations
of more than 10,000 units are rarely, if
ever, required even for high-throughput
operations.
Companies also conduct longer dura-
tion fills to test operator fatigue. During
the past 25 years, industry has conducted
media-fill tests under a wide variety of con-
ditions, including so called “piggy-back”
media fills done at the end of a normal
production fill. There is no evidence indi-
cating that operator fatigue is a factor in
environmental control, media-fill outcome,
or product safety (17). Nevertheless, there
is no need to fill enormous quantities of
media for this sole purpose of evaluating
fatigue because the more automated an
aseptic operation is the less likely fatigue
will be an issue in asepsis. Each firm should
perform risk analysis to ensure that their
media-fill tests are representative evalua-
tions of their processes, adjusting media-
fill sample size accordingly.
There should be no fixed requirement
for each operator to participate in a
media-fill test before being admitted to
aseptic production work. Abundant means
exist to qualify personnel for aseptic op-
erations without the requirement for at
least one media-fill test. Each employee
can be evaluated in terms of gowning ef-
fectiveness, and laboratory simulations
can be used to evaluate their aseptic tech-
nique (6, 8). In addition, operators can be
comprehensively trained on equipment
operations and relevant operating proce-
dures and work instructions. Critical per-
sonnel, including those required to per-
form equipment set-up and critical aseptic
assembly, should be required to success-
fully participate in a media-fill test before
taking up their work assignment.
There is no need to conduct more than
one media-fill test per operational shift
per year. More-frequent media fills on val-
idated production lines are unnecessary.
136 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
It is also unnecessary to test each container ally is. It is important to remember that a Modern aseptic cleanrooms are outstand-
type each year. A firm should develop a media-fill test is a snapshot in time and is ing, but they are not perfect. The quaran-
rationale for their container/closure sys- not always predictive of future outcome tine or disposal of safe product because of
tem selection on the basis of a careful or informative regarding previously man- unwarranted concerns about “sterility as-
analysis of risk (6). ufactured product. Certainly a zero con- surance” is wasteful and not scientifically
Media-fill tests are quite useful, but they tamination target is appropriate and supportable. Documented improvements
are not without limitations. Media-fill re- media-fill positives should occur rather in aseptic processing performance are
sults can lead a firm (or a regulatory in- rarely. However, this does not mean that somewhat difficult to support in a quan-
spector) to conclude that an operation is a single contaminated unit should be the tifiable manner. One measure of industry
much better or much worse than it actu- cause of product quarantine or rejection. performance is the increasingly tighter
limits placed on media fills since 1980 (see
Table II).
That firms are voluntarily reducing their
acceptance criteria for media-fill contam-
ination rates below 0.1% supports the con-
tinued improvements that have been made
to aseptic processing. A comparable as-
sessment can be found in USP, where a
recommendation has been made that two
out of three media fills should be devoid
of contamination (20). Coupled with the
near absence of documented evidence in-
dicating the presence of actual microbial
contamination in sterile products, this sug-
gests that sterile products manufactured
by aseptic processing are safer than ever.
Summary
We believe that aseptic processing in our
industry has improved markedly since
1988, including
• improved cleanroom garments and a
better understand of modes of con-
tamination
• improved cleanroom designs and op-
148 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com
erational performance from microbial contamination will be even Environmental Monitoring Data: Does a
Worst Case Time for Monitoring Cleanrooms
• more comprehensive employee train- better controlled than they are today. After
Exist?” PDA J. Pharma. Sci. Technol. 52 (6),
ing and qualification programs. all, the only significant source of contam- 326–330 (1998).
• improved aseptic processing equip- ination is widely recognized, and there are 18. J. Agalloco and J., Akers, “Validation of Asep-
ment requiring fewer line interven- superb methods for minimizing this risk tic Processing,” in Encyclopedia of Pharma-
tions even further than is possible today. ceutical Technology, J. Swarbeck and J. Boy-
lan, Eds. (Marcel-Dekker, New York, NY,
• well-established validation programs
2001).
incorporating sound change-control References 19. J. Agalloco, “The State of Current Industry
practices to ensure continuing relia- 1. J. Akers et al., “A Review of Current Technol- Practice: Results from the PDA 2001 Survey
bility of the processes ogy in Parenteral Manufacturing,” J. Par- on Aseptic Processing,” in Proceedings of PDA
enteral Sci. Technol. 42 (2), 53–56 (1988). Spring 2002 Meeting (March 2002).
• implementation of advanced contam- 2. FDA, “Guideline on Sterile Drug Products 20. USP ^1116& “Microbial Evaluation of Clean
ination control technologies such as Produced by Aseptic Processing” (1987). Rooms, Isolator Environments Used for the
isolators, restricted access barrier sys- 3. J. Agalloco and B. Gordon, “Current Prac- Manufacture of Aseptically Manufactured
tems (RABS), and blow–fill–seal or tices in the Use of Media Fills in the Valida- Sterile Drug Products and Other Controlled
form–fill–seal systems. tion of Aseptic Processing,” J. Parenteral Sci. Environments,” Pharmacopeial Forum 25 (3),
Technol. 41 (4), 128–141(1987). 8264–8279 (May–June 1999).
The industry as a whole has earned an 4. J. Agalloco and J. Akers, “Current Practices 21. ISO 14644-1, “Cleanrooms and Associated
enviable safety record in aseptic process- in the Validation of Aseptic Processing 1992,” Classified Environments” (2001).
ing over the years. In 1988, aseptic tech- J. Parenteral Sci. Technol. 47 (2), supplement 22. Federal Standard 209E, 1992, withdrawn
nologies operating in compliance with in- (1993). 2001.
dustry and regulatory guidelines resulted 5. J. Agalloco, “Microbiological Evaluation and 23. ISPE Guideline, Sterile Manufacturing Facil-
Monitoring of Cleanroom Environments ” ities (1999).
in product that was unquestionably and J. Parenteral Sci. Technol. 47 (4), 152-154 24. J. Akers and J. Agalloco, “Environmental
unequivocally safe with respect to micro- 1993. Monitoring: Myths and Misapplications,”
bial contamination. Today, as in 1988, the 6. J. Agalloco et al., “Process Simulation Test- PDA J. Pharma. Sci. Technol. 55 (3), 176–184
weakest link in the sterile and aseptic prod- ing for Aseptically Filled Products,” PDA (2001).
uct delivery pathway is at the level of ad- Technical Report No. 22, PDA J. Pharma. Sci. 25. B. Reinmüller, “Dispersion and Risk Assess-
Technol.Vol. 50, No. 6, supplement, 1996. ment of Airborne Contaminants in Pharma-
ministration rather than manufacturing. 7. Agalloco, J., Akers, J., “Current Practices in ceutical Clean Rooms,” Bulletin No. 56 (Royal
Logically, those concerned with patient the Validation of Aseptic Processing – 1996,” Institute of Technology, Building Services
safety would seem better advised to focus PDA Technical Report No. 24, PDA J. Engineering, 2001).
their energies where they are likely to have Pharma. Sci. Technol. Volume 51, No. 2, sup- 26. J. Moldenhauer et al., “Fundamentals of an
the greatest effect. plement, 1997. Environmental Monitoring Program,” PDA
8. J. Agalloco, J. Akers, and R. Madsen, “Cur- Technical Report No. 13, PDA J. Pharma. Sci.
There have, of course, been recent re- rent Practices in the Validation of Aseptic Technol. 55 (5), supplement (2001).
ports of firms releasing aseptically Processing: 2001,” PDA Technical Report No. 27. J. Aydlett, Proceedings of PDA Seminar on
processed products that purportedly lack 36, PDA J. Pharma. Sci. Technol. Vol. 56, No. Aseptic Processing (2000).
sterility assurance. We do not doubt that 3, 2002. 28. J. Lindsay, “Experience in Media Fills at PDA
in very rare instances product has been 9. S.S. Block, “Definition of Terms,” in Disin- TRI,” poster presentation at PDA Spring 2002
fection, Sterilization and Preservation, S. Block, Meeting.
made in a manner contrary to good con- Ed. (Lippincott, Williams and Wilkins, 5th 29. J. Akers and J. Agalloco, “Isolators: Validation
tamination control practice. However, it ed., Philadelphia, PA, 2001). and Sound Scientific Judgment,” PDA J.
is inappropriate to punish the many for 10. T. Meltzer et al., “Filter Integrity Testing in Pharma. Sci. Technol. 54 (2), 110–111 (2000).
the sins of a very few. Those firms lacking Liquid Applications Revisited: Part I,” 30. J. Akers et al., “Design and Validation of Iso-
the commitment to manufacture “sterile” Pharma.Technol. 25 (10), (2001) and Part 2 lator Systems for the Manufacturing and Test-
Pharma. Technol. 25 (11), (2001). ing of Health Care Products,” PDA Techni-
products in an appropriate manner should 11. USP ^1116& “Environmental Control of Asep- cal Report No. 34, PDA J. Pharma. Sci.
have known better. Successful production tic Processing Environments” (US Pharma- Technol. 55 (5), (2001). PT
of “sterile” products using aseptic process- copeial Convention, Rockville, MD).
ing can certainly be made possible if the 12. Annex 1, EU GMP Directive, “Manufacture
precepts outlined within this article are of Sterile Medicinal Products” (1996).
13. “Sterilization in the 1990s,” in PDA/PMA Pro-
ascribed to. ceedings of Joint Conference (1990). Please rate this article.
Perfection in aseptic processing is not 14. J. Akers, J. Agalloco, and R. Madsen, “Moist On the Reader Service Card, circle a number:
currently achievable, because an absolute Heat Sterilization: Myths and Realities,” PDA 348 Very useful and informative
demonstration of unequivocal sterility as- J. Pharma. Sci. Technol. 52 (6), 1998. 349 Somewhat useful and informative
surance is not possible. However, safety is 15. J. Robertson et al., “Sterilizing Filtration of 350 Not useful or informative
Liquids,” PDA Technical Report No. 26, PDA
both possible and routinely attained, and J. Pharma. Sci. Technol. 52 (1), 346–350
Your feedback is important to us.
for that industry can be proud. Industry (1998).
understands that continuous process im- 16. J. Agalloco, J., “Intervention/Incubation Prac-
provement in our performance, especially tice” (under consideration for insertion in
in the production of “sterile” products is TR No. 22) in Proceedings of the PDA Spring
2002 Meeting (2002).
not just desirable, but essential. We have 17. A.M. Cundell et al., “Statistical Analysis of
no doubt that in the coming decades risks
150 Pharmaceutical Technology OCTOBER 2004 www.phar mtech.com