The Future of Aseptic
Processing
Sterility by Design
Dr. James E. Akers
Technical Advisor
Shibuya Kogyo, Co. LTD.
1
Japan PDA 2013
Background
Sterility by Design is a concept Mr. J. Agalloco and I began developing
in 2006 and has since been the subject of articles and two text book
chapters now in the press.
Its development was a joint effort in which we built on years of
discussion and extensive collaboration on the subjects of aseptic
processing, sterilization, and sterility assurance.
It also was influenced by our work on the Akers-Agalloco risk analysis
approach.
It was further influenced by work done by Dr. Katayama and
colleagues in Japan on aseptic risk and quality assessment.
2
Validation- Test? Monitor? or
Design?
In the 1970s, when validation was first being introduced
part of the rationale was the understanding that “quality
cannot be tested into products it must be designed and
built in to products.
In aseptic processing the standards appear to be built on
the idea that quality (sterility) can be monitored into
products.
The concepts central to validation included the idea that
once process designs were shown to work in practice
through effective design and performance qualification,
less testing would be necessary.
3
The Quality by Design
Concept

Is not new- it was introduced by J.M. Juran in a book published in
1992.

Juran thought that any new product was a “Hatchery” for quality
problems.

Juran focused on “Gaps” relating to what a customer actually
needs, what the supplier thinks the customer needs, what the
supplier designs, and finally what the supplier delivers.

Juran was concerned about an understanding “Gap” between what
the customer needed and what an organization tried to supply.

Juran taught us that the key element of quality is fitness for use.
4
The Sterile Product
Customer
 The customer in this case may be the healthcare provider and/or
the patient.
 What is required are:
① Products which are effective
② Products which do not result in infections, fever, or other
toxemias.
③ Is this consistent the producer’s understanding of aseptic product
requirements? The regulatory requirements?
5
Are Regulations and Standards
Aligned with the Customer’s
Needs?
 To answer this question we must ask if what we do to ensure
safety provides value to the customer (patient)?
① Does environmental monitoring provide safety to the patient?
② Does the sterility test provide value to the patient?
③ Do media fills provide safety to the patient?
Are there other means of assuring the same or higher level of safety
at a lower cost?
6
Are Sterile Products
manufactured by Industry Safe?
 Researching back to 2001 I was unable to find any evidence of
sterility failures involving sterile products manufactured by industry
(pharma/biopharma).
 In the USA alone we average according to the Centers for Disease
Control about 1.7 million hospital acquired infections (HAIs) per year
(2010 data).
 About 95,000-100,000 of those who contract HAIs in the USA die.
 In Europe ~25,000 die of HAIs each year
 Japan averages about 90,000-100,000 nosocomial infections per year.
7
There is a big problem with
patients becoming infected
during medical treatment!
 It seems from the available data that industrially produced sterile
and aseptic sterile products are not a significant source of risk.
 A quality expert might conclude that to serve the customer of
healthcare there should be more focus on infection control in
direct patient care.
 But spending more resources and money on controlling sterile
product manufacturing is not money well spent.
 Perhaps, particularly in the USA and Europe we have a “quality
gap” as Juran would say and we are spending too much of our
resources on aspects of healthcare that can be shown to provide
little customer benefit.
8
“The Regulatory Spiral”
 The Regulatory Spiral is a phrase coined by Mr. John Sharp in the
late 1990’s while he was working for the UK Medicines Control
Authority.
 In the Regulatory Spiral each technological advance introduced
results in regulators responding to this “new state of the art” by
tightening standards.
 The result is an ever growing and tightening spiral of as Mr. Sharp
put it “increasingly demanding standards”.
 Mr. Sharp speculated that this spiral might be kicked-off by
companies wishing to gain advantage or by over zealous
inspectors.
9
The Regulatory Spiral and
Aseptic Processing
 There has been a regulatory spiral associated with aseptic
processing and it has had the following effects:
① An ongoing increase in Environmental Monitoring sample
intensity
② An ongoing tightening of acceptance criteria for both EM and
media fill tests.
③ Increasingly more complex air visualization studies
④ Difficult and costly validation requirements for advanced
technologies in spite of their clear safety/risk reduction
advantages.
⑤ And others as well!
10
Current aseptic standards and regulations are:
Based on the premise that it is possible to both test and monitor quality into aseptically
produced products.
Even though risk and contamination rate data indicate that aseptic processing
performance (safety) is better than ever before microbiological test requirements continue
to increase.
The industry is essentially being asked to test and monitor sterility into the products,
perhaps more than ever before.
There has been little discussion about how to use initiatives such as PAT or QbD in
aseptic processing.
The validation requirements for isolators and other advanced aseptic processing has not
been reconsidered to reflect technology improvements.
Validation of advanced technologies parallels the requirements for human-scale clean
room aseptic processing even as those requirements continue to evolve and require more
testing, validation studies and ongoing monitoring.
11
The regulatory spiral continues
without consideration of the
following facts:
We can’t prove that sterility exists in aseptic processingthere is no amount of testing or monitoring that would
enable us to prove sterility.
The proof of sterility would require us to take a sample of
infinite size (volume) and test it with an analytical method
that had a limit of detection of zero.
This method would also have to have perfect sensitivity
since it would have to detect all potential contaminants.
Scientific experience and wisdom informs us that this
approach is a dead end.
12
It is necessary to stop and
reverse the regulatory spiral
 We should rely on engineering to specific defined principals and
demonstration of compliance with user requirements
specifications in place of microbiological testing and monitoring.
 It is possible to define the physical performance conditions that
must be present for the safety of aseptic products to be assured.
 With proper design, execution and validation of advanced
technologies against defined specifications microbiological testing
and monitoring are not required.
 Given the limitations of microbiological methods they do not
provide useful information with most modern technologies
including state of the art clean room designs.
13
Aseptic Processing is not in
2013 a difficult challenge
 It is not difficult to design a modern aseptic operation that
provides Sterility by Design.
 There are only a few key factors that must be carefully
specified and controlled.
 Where advanced aseptic processing technologies are used
the major risk, human contamination, is effectively
eliminated by the inherent features of the design.
 Therefore, all we need to is bring sterilized product,
containers and closures together in a microbial
contamination free environment.
14
Sterility by Design in Cleanrooms
Thorough design and execution makes microbiological testing less significant.
Equipment Design
Facility
Design
Personnel Traffic
Flow
HVAC
Disinfection
Environment
Equipment
Storage
Conditions
Validation
Product
Personnel
Practices &
Training
Product &
Material Flow
Cleaning &
Maintenance
Procedures
Product & Materials
15
Sterilization
Microbial Proliferation- An
Objectionable Condition
 Any proliferation of microorganisms in a facility or process is an
objectionable condition.
 It is critical to have product knowledge regarding the characteristics
of each product.
 Products of natural origin such as proteins or peptides can support
microbial growth.
 Dry powders with low moisture levels, products with high ionic
strength, are at pH’s lower than about 3 or high than 9, or products
that are inherently antimicrobial are generally inherently safe from
microbial proliferation.
16
Microbial Contamination and Harmful Effects to
Product

Microbial Contamination Could:

1. Destroy the intrinsic quality of a product by causing damage to the
product such that its efficacy is lost in part or completely.

2. Product Harmful Side Effects in the form of potential to cause in
infection or toxemia.

In order for a microbiological contamination event to cause toxin
formation that could result in harmful effects to patients, or could
damage product efficacy the following condition must be met:

Microorganisms must proliferate in the product or its ingredients in
sufficient numbers to result in the production of toxins, or damage
active ingredients resulting in degradation of the product. NO
PROLIFERATION = NO TOXIN AND NO PRODUCT DAMAGE.
17
6
Conventional Aseptic Processing
can produce safe products
Aseptic processing has been performed since its beginnings under conditions
that could never be demonstrated to be ‘sterile’.
As as long as the contamination risks are understood, and measures taken to
minimize them aseptic products made in human scale clean rooms are very
safe.
Conditions required to produce safe products are easy to understand and
accomplish.
Safety depends on an environment in which organisms cannot proliferate,
well-trained operators, equipment that is sufficiently automated so that the
most difficult interventions are eliminated, an environment will HEPA
filtered air at high air exchange rates, highly retentive clean room gowns.
Advanced technologies, however, make it easier to design facilities and processes
for aseptic manufacturing because they have inherently higher contamination
control and risk mitigation capabilities.
18
Absolute Sterility
 The regulatory spiral over the last 20 years makes it appear that
absolute sterility has been a regulatory objective.
 We know though that absolute sterility can certainly not be
attained in clean rooms with direct human intervention.
 This raises the question as to whether products filled on aseptic
processes only capable of the historically required 0.1%
contamination rate pose a medical risk.
 The answer seems to be no- provided of course there is no
microbial growth in the product container.
 The data regarding product contamination and medical risk
makes in reasonable to ask if some regulatory ideas are cost
effective given their limited effect on patient risk?
19
Examples of Requirements that
are unlikely to reduce risk to
patients.
 Air visualization studies using various types of smoke generation in
ISO 5 environments- no relationship has been scientifically make with
contamination risk mitigation.
 Placement of cap seaming systems for vials in EU Grade A, or ISO 5
environments, because this has never been identified as a source of
contamination in process simulation tests.
 Increasing EM sampling frequency and sampling locations- because
there is no evidence that more EM corresponds to better
contamination risk management. In ISO 5 environments
contamination rates do not vary with exposure and are typically
>99% negative (zero CFU)
 Larger media fill samples and processing times, because the increases
in media fill sample size to sometimes 20,000 or more and longer run
times has not resulted in more positive units being observed.
20
Sterility Assurance-Points to
Consider-1
 Sterility
is the absence of organisms capable of
replicating- given statistical limitations there is no way
to directly demonstrate sterility.
 Sterility assurance is by convention the probability that
the condition of sterility exists in a material- in
terminal sterilization we can calculate a true SAL in
aseptic processing we cannot we can only estimate a
minimum rate of contamination.
21
Sterility Assurance Points to
Consider-2
 There are three ways we attempt to evaluate “sterility assurance” in aseptic
processing:
①
Process simulation or media fill tests
② Sterility testing which is severally limited statistically and in terms of
analytical sensitivity.
③ Environmental Monitoring which does not directly test product and is limited
both statistically and in terms of analytical sensitivity.
 All three listed methods are attempts to test or monitor sterility into the
process and are not acceptable proofs of sterility assurance no matter how
intensive we make the testing or how low we try to push analytical sensitivity.
 In spite of much discussion Rapid Microbial Methods will only get results
faster, they will only marginally (if at all) improve sensitivity.
22
Engineering Product Safety
(sterility assurance)
 Design and Construction of Manufacturing facilities and
environment
 Selection, Design and Construction of aseptic processing
systems based on appropriate technologies
 Package engineering of drug delivery systems and
containers.
 Formulation development and sterilization of product prior
to fill
 Design of product filtration skids, storage vessels and
product delivery to aseptic fill system including CIP/SIP.
23
Containers and Closure Systems
Quality is often Overlooked
Higher AQLs for defects can result in fewer component feed faults and fewer
interventions/adjustments
24
Sterility by Design
 Engineering of quality into process as described by J.M Juran is not a new idea.
 However, the risk assessments we are doing in industry are not built on an
engineering platform that will result in better outcomes.
 We do not need risk assessment based upon unscientific models we need risk
mitigation based upon process and product knowledge and sound engineering
principles.
 We are wasting time, resources and money attempting to test sterility into our
aseptic processed drugs and biologics
 With newer advanced aseptic technologies testing and monitoring will become
even less significant.
 We must find more efficient approaches relying on the establishment of sound
physical operational principles based upon URS derived from sound engineering
and scientific principles
25
Concluding Thoughts
 FMEA based risk analysis is a popular concept now, but it
has contributed nothing new to aseptic processing
technology.
 This is because the assumptions often made for risk levels
and criticality are based upon incorrect concepts.
 This can readily be seen by the comparatively high risk seen
associated with for example isolator decontamination which
is actually a minor risk component.
 Improvements in aseptic processing will come from better
engineered processing systems and we will not be able to
measure these improvements using media fills or EM.
26
Improvements in Aseptic
Processing always come from:
 Utilizing automation to reduce reliance on personnel for
routine and corrective interventions.
 Applying separative technologies such as barriers or
isolators to eliminate human contamination from the critical
production zone.
 It follows that the future of aseptic processing rests with full
separated and fully automated systems that can be run from
a control room with no direct human interaction with the
process during aseptic filling, packaging or assembly.
27
Thank you for your
kind attention!
28