See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/303820785

Risk Assessment for Intervention Scoring in

Relation to Aseptic Processing

Article April 2016

CITATION READS

1 38

1 author:

Tim Sandle
The University of Manchester
279 PUBLICATIONS 229 CITATIONS

SEE PROFILE

All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Tim Sandle
letting you access and read them immediately. Retrieved on: 23 August 2016
Risk Assessment for Intervention
Scoring in Relation to Aseptic
Processing | IVT
By
Tim Sandle, Ph.D.

Apr 22, 2016 7:00 am PDT

Peer Reviewed: Risk

Introduction

Aseptic processing is arguably the most 'at risk' pharmaceutical process in terms of
microbiological contamination (1). This is because the final point in the production
process is during filling, stoppering and capping and oversealing. Because of the
nature of the product, after these activities have taken place the product cannot be
subjected to any sterilization process. Thus, excluding concerns with the sealed
container and container closure integrity issues, if microbial contamination enters at
the filling stage no other process steps can be undertaken to remove or destroy the
contaminant.

Product protection exists by using a sterile filtered product and the use of
depyrogenated glassware and sterile stoppers. In addition, the activity of filling takes
place within an ISO class 5 (EU GMP Grade A) localized airflow. With the clean air
zone, additional protection exists through the use of isolator technology, which adds
a complete barrier and stops the risks associated with personnel intervention from
occurring (2).

Although isolator technology is becoming more widespread, other types of aseptic

processing technology requires occasional personnel intervention (3). The need for
human ingress into the protective zone often exists with a conventional
unidirectional airflow device. Here machine doors may sometimes need to be opened
to extract a fallen vial or stopper (although such 'open processing' is these days not
considered to be suitable cGMP and where it exists it should be being considered for
replacement). Even with gloveport devices, as might be found with Restrictive Access
Barrier Systems (RABS) and Limited Access Barrier Systems (LABS), occasional
forays into the aseptic zone may be required.

Each human intervention is a risk, because people are the primary source of
microbial contamination and personnel activities and behavior are the hardest to
control. No intervention carries a zero risk and it follows that interventions are not a
good thing; thus every opportunity, through good design, appropriate machine set-
up, and efficient machine running, should be taken to avoid them from happening
during a filling run (4).

While there are control mechanisms in place, most importantly the direction and
velocity of the airflow (which needs to be confirmed by an airflow visualization
study), together with personnel training (glove sanitization and using sterile
implements to avoid direct touching of components), risks from interventions will be
ever present. In assessing risks, the standard verification tool of environmental
monitoring is too limited to give complete assurance (due to the limitations
pertaining to the metrology of the methods) (5). There is a touch of irony that some
of the interventions are the very act of environmental monitoring.

While each aseptic intervention carries a risk, it is down to the aseptic processing
manager and the microbiologist to agree the level of risk. This requires three
questions to be addressed. First: are all interventions of equal risk?; secondly, how
can multiple interventions be evaluated? And thirdly, at what point does a further
intervention become one ingression into the aseptic core too many? Those tasked
with running aseptic filling lines or reviewing the filling runs for batch release need
to be confident that these questions have been posed and answered. This paper
presents one possible approach through which these questions can be answered. This
is through a risk scoring system.

Certain medicinal products need to be sterile at the point where they are introduced
to the patient by injection. This is because this mode of drug delivery bypasses the
body's natural defenses. Because of this, the administration of many biologics carries
a higher risk of infection being introduced to the patient compared with, say, an oral
drug product. Sterile drug products can be manufactured using two techniques:
terminal sterilization or aseptic processing. With terminal sterilization, the product
in its final container is subject to a final sterilization processes. This ordinarily
involves heat or irradiation.

While capable of providing a predictable level of sterility assurance, terminal

sterilization is not suitable for many biologics. This is because many such products
will be inactivated or destroyed by exposure to heat or irradiation. This means there
is a need for many products to be manufactured in an aseptic manner. Moreover,
many pharmaceutical companies are changing product profiles as conventional large
molecule chemical entities are replaced with more biologically derived products. This
has led to an increase with the manufacturing using aseptic processing.

In an aseptic process, the drug product and container/closure are subjected to

sterilization methods separately, as appropriate, and then brought together. This
takes place under an aseptic environment, where the aseptic environment is
separated from the general environment by some form of barrier. The aseptic
environment is ISO class 5 (EU GMP Grade A) in operation and the surrounding
environment is ISO class 7 (EU GMP Grade B) in operation.

Interventions
Interventions in any aseptic process should be far and few between. Quality Risk
Management (QRM) and Quality by Design (QbD), as two key regulatory initiatives,
should lead to the development of processing systems where interventions become a
rarity.

Although modern pharmaceutical manufacturing operations are well designed

sometimes operational aspects go wrong. Vials can fall over, stoppers can jam and so
forth. Ideally these are addressed through manipulations via gloveports (with fitted,
sterile gauntlets). With isolation technology, the only means to access the aseptic
zone is via a gloveport and any opening of the isolator doors brings the process to an
end. For a well-designed system, there should be no need for any activity other than
through a gloveport.

For other barrier systems, while gloveports are the norm, older style machines exist.
Even with gloveport equipped barrier systems, the need for an occasional
intervention arises (6). The risks associated with such interventions require
evaluating, through both airflow visualization studies (7) and media simulation fills
(8). In relation to this, the FDA aseptic filling guidance emphasizes that the
"evaluation of the impact of aseptic manipulations (e.g., interventions)" is required
(9).

The guidance also states:

"Any intervention or stoppage during an aseptic process can increase the risk of
contamination. The design of equipment used in aseptic processing should limit the
number and complexity of aseptic interventions by personnel."

Where interventions are required, the activity produces several factors that need to
be considered and evaluated:

a) Are all interventions of equal risk?

b) Does the risk change should multiple interventions be performed in a given filling
run?

c) Ho many interventions can be performed before the risk becomes too great and
consideration needs to be given to terminating the filling run?

This paper presents an approach to evaluate the risks stemming from interventions.

Intervention risks

By risks, this is a reference to the possibility of microbiological contamination (19).

The ingress of a microorganism into an aseptically filled medicine presents a risk to
the patient. This is because the microorganism may be capable of growth in the
product; the microorganism may be capable of producing a toxic by-product; or the
microorganisms in itself may present a risk to an immunocompromised patient.

Microbial risks will arise from air (with microorganisms carried on particles, like skin
detritus) and from direct transfer (such as from the gloved hands of personnel). The
 opportunities for microorganisms to enter a product vial or land onto a critical
surface relate to the factors of dispersion, transfer and deposition (11). To an extent,
such risk factors can be modeled and then designed out through assessing assess the
transfer of contamination from all of the sources within the cleanroom area that
could impact upon the aseptic zone; and then assessing both air and surface contact
contamination from these areas within the aseptic zone.

To help with post-filling evaluations, Whyte and Eaton have outlined a number of
useful equations. For example, to assess the overall risk of microbial contamination
of a product (12):

No. of microbes deposited on a product =C S P P A T

d a

Where:

C = concentration of microbial contamination on, or in, a source (number/cm for a2

surface, or number/cm for air);

3

S = the quantity of surface material, or air, that is dispersed, from a source in a given
time (cm2 /s for surfaces, and cm3 /s for air dispersion); this can also be expressed
as the quantity dispersed per frequency of occurrence;

P = proportion of microorganisms dispersed from a source that are transferred to

d

the area adjacent to the product;

P = proportion of microorganisms in the adjacent area that are deposited per unit
a

area of the product (/cm ); 2

A = area of surface onto which microbes are deposit (cm ); 2

T = time, during which transfers occur(s); this can also be expressed as frequency of
occurrence.

Such risk assessment systems, based on fundamental models of microbial

contamination, allow for an effective risk assessment to be conducted when
considering the release of the product.

However, what about during the filling operation? When does the risk from
interventions present a problem for the continuation of filling? The paper presents
an intervention scoring approach.

Before doing so, there are some important activities to follow.

Defining an intervention and key steps

It is important to define an intervention and to differentiate it from a manipulation

through a gloveport gauntlet. An intervention during aseptic filling as the act of
opening the filling machine doors, whereby the Grade A / ISO class 5 protective zone
is exposed to the Grade B / ISO class 7 support area. Manipulations, especially via
RABS and LABS devices, are not risk free. There will always be concerns about glove
sterility and integrity.

Where filling machine doors are opened, the exposed vial(s) should be identified (or
marked up) and included in the sterility test set. Most sterility test failures are the
result of a personnel intervention (13).

Additionally, the operators should take finger plates, this allows an assessment to be
made of any contamination transfer from operator to critical surface to be made.
Importantly, all interventions mist documented. Such information is necessary for
the final batch review.

Intervention scoring

In devising a risk based intervention system, an assessment of a number of factors is

required. With this, and any risk based system, professional judgement plays an
important role in the final assessment. Either a qualitative of quantitative approach
can be adopted; the example quoted here uses a numerical system.

The use of a numerical score not only allows for a decision to be made as to the
relative and absolute risk of any intervention, it also allows different filling
operations to be compared and trended if necessary. The use of a numerical score
also allows a cut-off value to be applied. A cut-off value is a score which, when
exceeded during the filling runs, indicates to the filling team that a decision is
required whether filling should continue.

Devising a scoring system

The first step in developing an intervention scoring system is to devise the numerical
ranges. Once developed, different types of interventions can be assigned.

The scoring system used in the example weights each intervention based on the
perceived contamination risk to product or product components. The greater the risk
then the higher the score assigned. The risk scores used are in multiples of 5, with 0
being of minimal risk, up to 30 for the highest risk. Of course, other scoring systems
can be selected. This is detailed in the table below:
 Table 1: An example intervention scoring system

The above scoring system was based on accounting for three factors:

1. The location within the filling machine where the intervention takes place. Here it
is recognised that different parts of the filling machine pose different risks to exposed
vials.

The point of fill, for example, presents a bigger risk of contamination ingress than a
partially stoppered vial.

2. The height at which the intervention takes place relative to working height. Here,
working height, which is equivalent to the product vial, presents a bigger risk than a
height below the vial. This is because below the vial the unidirectional airflow is more
likely to sweep contamination away.

In relation to points '1' and '2' above, some aseptic processing managers adopt the
terms 'critical' and 'non-critical' interventions in relation to height and position. By
this, it can be inferred:

Critical intervention: when the body/ glove is exposed above (within vertical
unidirectional air- flow) open vials/ hopper / product contact surfaces and disrupts
unidirectional air flow. Actions in response may include line clearance.
 Non-critical intervention: the gloves or body parts are not disrupting the
unidirectional air flow. It is performed with sterile tools above the open vials/ above
hopper/ product contact surfaces; stopper bag addition, bulk container addition.

While these differences are important, the phrases 'critical' and 'non-critical' can
detract from the potential risk that any intervention presents to the process.

3. Time and complexity taken to complete the intervention. This informs whether an
intervention is classed as a major (of more complexity or taking a relatively longer
time) or minor (undertaken within a short time or of a relatively less complex
nature).

In assigning scores, the use of tools, such as using or not using forceps to remove a
vial, is not addressed since such activities are undertaken by using gloveports and
they are classed as manipulations. With developing scores, especially in relation to
time and complexity, useful information can be obtained from media fills, such as
from the viewing of digitally recorded footage (14).

Following this, the scoring system can be matched up with different types of
interventions. This is presented in Table 2 below. Table 2 takes the intervention score
table and pairs the score options with common types of interventions. A rationale for
the score selection is also provided, in the end column.

Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
Placement of air A Y 0 This activity has not been
sampler assigned a score because it takes
place during every filling
operation (once or twice at
defined locations depending
upon the length of the fill). The
activity is practiced during each
media trial. Therefore, cters
pribus (Latin for other things
being equal); it is not
considered to be a variable risk.

Placement of B Y 0 This activity has not been

settle plates assigned a score because it takes
place during every filling
operation (once or twice at
defined locations depending
upon the length of the fill). The
activity is practiced during each
media trial. Therefore, cters
pribus, it is not considered to be
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
a variable risk.

Addition of C Y 0 This activity has not been

sterilised assigned a score because it takes
stoppers to bowl place during every filling
operation (once or twice at
defined locations depending
upon the length of the fill). The
activity is practiced during each
media trial. Therefore, cters
pribus, it is not considered to be
a variable risk.

The operator who performs this

task is regularly assessed during
each filling operation through the
taking of their finger plates. To
date the data collected does not
suggest that this is a significant
risk.

Machine set up D Y 0 This activity has not been

prior to fill assigned a score because it takes
place during every filling
operation (once or twice at
defined locations depending
upon the length of the fill). The
activity is practiced during each
media trial. Therefore, cters
pribus, it is not considered to be
a variable risk.

This activity is not directly

related to the fill, however, it
could theoretically increase the
bioburden to the filling machine.
This is assessed through the
operators taking finger plates
after the cessation of the activity.
In addition, settle plates are
exposed during the set-up for
media trials which provides
information relating to the likely
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
settling of any viable particles.
To date both the finger plates and
the media trial settle plates have
been satisfactory and do not
suggest a significant risk from
this intervention.

Interventions D1 N The score assigned Occasional interventions are

during the period is dependent upon required between the set-up of
following the type of the filling machine and the start
machine set-up intervention (the of fill. It is recognised that this
and the start of score given is for represents an intervention into
fill the operations the Grade A / ISO class 5zone
listed below). and after a point where the
machine has been cleaned.
Should 3 or Different types of interventions
moreinterventions will score higher depending the
occur during the nature of the activity and the
period following duration.
machine set-up
and the start of
filling or the score
exceed 50, filling
should not
commence until
the fill supervisor
has discussed the
matter with
aqualified person.

A major
intervention may
require a re-set up
of the machine and
all of the
appropriate
environmental
monitoring to be
undertaken.

All interventions
will be assessed by
a review of
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
microbiological
data post fill (a
review of
intervention finger
plates and exposed
settle plates)

Delay of fifteen E N/A 0 Removed (refer to discussion

minutes during section).
filling

Removal of F N 10 This intervention relates to a

fallen bottle manual intervention into the
where no line filling machine. A member of
clearance occurs staff will use a sterile implement
(such as forceps) to make an
adjustment or to remove an
object (such as a vial).

Typically this activity would take

less than five minutes. The
activity is also practiced during a
media trial (provided that the
activity has taken place within
the last six-months during the
filling run, in relation to the
specific filling line).

The score of ten is given because

the risk is higher than a machine
stoppage but lower than a full
line clearance.

Rotation of G N 10 This intervention relates to an

stopper gripper operation on the filling machine.
cam It does not involve touching any
vials and could be seen as a
lower risk than F. However, as
the operation occurs close to the
stopper bowl the risk is elevated
and a score of 10 is thus
appropriate.
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
Removal of H N 5 This intervention relates to a
jammed manual intervention into the
stoppered bottles filling machine. A member of
(outside of point- staff will use a sterile implement
of-fill area) (such as forceps) to make an
adjustment or to remove an
object (such as a vial).

Typically this activity would take

less than five minutes and the
line would be cleared. The
activity is also practiced during a
media trial (provided that the
activity has taken place within
the last six-months during the
filling run, in relation to the
specific filling line).

A lower score is given than

intervention F because this
intervention would only occur
after vials have been stoppered
and transported away from the
point of fill and stoppering area.

Pressing down I N 10 This intervention relates to an

load cell operation on the filling machine.
It does not involve touching any
vials and could be seen as a
lower risk than F. However, as
the operation occurs close to the
point of fill the risk is elevated
and a score of 10 is thus
appropriate.

Removal of J N 10 This intervention relates to a

jammed manual intervention into the
stoppered bottles filling machine. A member of
by opening the staff will use a sterile implement
area at the point- (such as forceps) to make an
of-fill adjustment or to remove an
object (such as a vial).
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
Typically this activity would take
less than five minutes and the
line would be cleared. The
activity is also practiced during a
media trial (provided that the
activity has taken place within
the last six-months during the
filling run, in relation to the
specific filling line).

A higher score is given than

intervention H because this
intervention occurs close to the
point of fill.

Removal of K N 15 This intervention relates to a

jammed bottle manual intervention into the
at the point of fill filling machine. A member of
staff will use a sterile implement
(such as forceps) to make an
adjustment or to remove an
object (such as a vial).

Typically this activity would take

less than five minutes and the
line would be cleared. The
activity is also practiced during a
media trial (provided that the
activity has taken place within
the last six-months during the
filling run, in relation to the
specific filling line).

The score of fifteen is given

because the risk is higher than
intervention F due to the activity
taking place at the point of fill.

Stopper jammed L N 10 This intervention relates to a

in feedtrack manual intervention into the
filling machine. A member of
staff will use a sterile implement
(such as forceps) to make an
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
adjustment or to remove an
object (such as a vial).

Typically this activity would take

less than five minutes and the
line would be cleared. The
activity is also practiced during a
media trial (provided that the
activity has taken place within
the last six-months during the
filling run, in relation to the
specific filling line).

A higher score is given than

intervention H because this
intervention occurs close to the
stopper bowl.

Needle lift M N 15 This intervention involves

manipulating the filling needle
with a sterile instrument. As the
filling needle is a critical product
contact site a higher intervention
score is awarded relative to
interventions F, G, I, J.

Minor N N 10 Minor adjustment is defined as

mechanical an activity that does not involve
adjustment to the removal or replacement of
filling machine any machine parts and last for
less than five minutes. A score of
ten is awarded because the
activity could potentially take
place close to a critical product
surface, such as, the point of ill
or stopper bowl.

Major O N 30 Major adjustment is defined as

mechanical an activity that does involve the
adjustment to removal or replacement of any
filling machine or machine parts and last for more
change to a than five minutes. A score of
critical thirty is awarded because the
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
component (such activity could potentially take
as a stopper place close to a critical product
bowl). surface, such as, the point of fill
or stopper bowl.

At first view the score would

simply be doubled, that is, seen
as twice the risk as intervention
N. However, because the
operator may need to work inside
the filling machine and could be
taking the machine apart, thereby
exposing additional surfaces, it
was considered that a score of
twenty was of insufficient
proportion given the nature of the
task.

Clearance P N 15 This intervention involves

ofdepyrogenation manually entering the filling
tunnel outfeed machine and removing a large
area number of vials. As this involves
placing an operator close to
critical product contact sites for a
significant amount of time
(probably longer than five
minutes) a higher intervention
score is awarded relative to
interventions F, G, I, J.

Calibration check Q N 20 A calibration check is normally

(during filling) performed before filling and it is
not classed as an intervention.
However, should a spillage occur
or the machine appears to
showing a fill problem a
calibration check is required. If
this is related to spillage then the
higher score for intervention T
would be given.

If a calibration check is carried

out for another reason
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
(intervention Q) a score of
twenty is given. This is a higher
score than intervention N
because of the long time taken to
complete this intervention
(typically longer than ten
minutes) and because the weights
used are not sterilised (although
they would be sanitised).

Spillage R N 20 The risk from a minor spillage is

clearance atpoint classed as a similar level of risk
of fill(classed to intervention Q. This is because
asminor) of the long time taken to
complete this intervention
(typically longer than ten
minutes) and because the
operator is disturbing the air
pattern at the point of fill and
there is a level of risk of close
contact with critical machine
contact parts (such as filling
needles).

Replacement of S N 30 This risk is far higher than

filling pump or intervention N because the
change to a activity lasts typically fifteen to
filling machine twenty minutes and involves
manifold for manipulation of filling needles.
other filling lines The risk is therefore of a greater
proportion than intervention.

Spillage T N 30 The risk from a minor spillage

clearance atpoint was classed as a similar level of
of fill(classed risk to intervention Q. However,
asmajor e.g. the score is higher with a major
involving spillage the long time taken to
removal of complete this intervention
machine parts) (typically longer than ten
minutes); because the operator is
disturbing the air pattern at the
point of fill; because there is a
level of risk of close contact with
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
critical machine contact parts
(such as filling needles); because
the activity could potentially take
place close to a critical product
surface, such as, the point of fill
or stopper bowl; and because the
operator may need to work inside
the filling machine and could be
taking the machine apart, thereby
exposing additional surfaces.
Therefore, it was considered that
a score of twenty was of
insufficient proportion given the
nature of the task and thirty
points was awarded.

Changing of the V Y 0 This activity has not been

stopper hopper assigned a score because it takes
place during every filling
operation on several occasions
when the filling machine in
P215A is used. The activity is
practiced during each media trial.
Therefore,cters pribus, it is
not considered to be a variable
risk.

Glove change W Y 20 The risk is negated by the glove

procedure for change being relatively short;
filling machines due to the intervention being
which have a practiced during media trials; due
glove port to the doors not being opened;
and due to no intervention being
made into the Grade A / ISO
class 5environment (should an
intervention into Grade A / ISO
class 5 occur, the intervention
appropriate to that activity would
be additionally scored).

Interventions on X Y 10 For interventions on glove ports

glove ports which which require the doors to be
require doors to opened, this requires the gloves
 Code

Justification
Intervention
type
Routine
task
Single
intervention score
of score
be opened to be changed. This is a relatively
low risk activity (due to this
activity being practiced for
media trials) and it is assigned a
score of 10.

Adjustment to or Z Y 20 Changing ppaper counter tubing

change of ppaper can be a major intervention based
counter tubing on the duration of the activity
and the closeness to the point of
fill

Table 2: Examples of filling machine interventions and assigned scores

Table 2 has presented the scoring system alongside different types of interventions.
The majority of these are corrective interventions, undertaken to allow the filling run
to continue. Such interventions will ideally have been practiced during media filling
trials and the way that each is performed should be described in an SOP and
appropriate training given to the operators (15).

This list of interventions presented in Table 2 is not designed to be exhaustive.

Should other types of interventions occur, that are not listed in the table, then
professional judgement is required as to the appropriate score, based on a
consideration of the risk. Care should be taken here, since an intervention that is not
listed is unlikely to have been performed during a media filling trial and thus will not
have been performed in a recent period of time. It will most likely carry a high risk.

With the above list, a cut-off value needs to be assigned. This is the total score from a
series of interventions taken to constitute a significant enough risk that filling should
be suspended. This is something that needs to be decided internally. Based on Table
2, a score of somewhere between 50 and 60 might be appropriate (although this
should not be taken as absolute),

Summary

Due to progressive advances with aseptic processing technology, human

interventions in aseptic filling, such as relating to maintenance, correction of jams, or
removal of fallen vials has significantly reduced. Nonetheless, with non-isolator
systems the need to occasional interventions remains.

Where possible interventions should be avoided and any intervention presents a risk.
While this paper presents a risk scoring system, the approach should not be used to
 discuss away the fact that interventions should be avoided. Nor should the approach
be used to assume all interventions have been perfectly executed. All operators are
capable of carrying out the most basic intervention badly, and the lower scores
presented in the table should only be taken following a review of a video recording of
the operation (all aseptic filling operations should ideally be digitally captured).

These issues noted, the paper has considered interventions in relation to aseptic
filling. While all interventions carry risks, the risks will vary according to the nature
of the operation and where within the filling machine the intervention occurs.
Furthermore, the more interventions undertaken the greater the risk presented to
the filling operation. Here the idea of an accumulative score over time develops. To
add to this, it is sensible to have a cut-off value - a point where, if exceeded, a
decision should be made to continue filling. Exceeding the cut-off value should not
simply be accepted, even if the risk to filled product is considered to be low.
Mechanical problems with the operation of filling machines should be addressed,
through continuous improvement initiatives, and measures put in place to prevent
repeat occurrences.

The paper has illustrated this by way of a case study example. The example has been
prepared for illustrative purposes only and it is not applicable to every filling
operation (each filling operation differs and, more importantly, each ISO class 5 /
Grade A clean zone is not identical in its design, performance or capability).
However, it can provide the basis for others to construct their own intervention
scoring system along similar lines.

References

1. Sandle, T. (2015a): Aseptic Transfer Risk Assessment: A Case Study, Journal of

Validation Technology, 21(1): 1-10
2. Sandle, T. (2004) General Considerations for the Risk Assessment of Isolators used
for Aseptic Processes, Pharmaceutical Manufacturing and Packaging Sourcer,
Winter 2004, pp43-47
3. Akers, J., Agalloco, J., Madsen, R. (2006) What is Advanced Aseptic
Processing?, Pharmaceutical Manufacturing, 4 (2): 25-27
4. Agalloco, J., and Akers, J. (2011) Revisiting Interventions in Aseptic
Processing, Pharmaceutical Technology, 35 (4): 69-72
5. Akers, J.E. and Agalloco, J. (2001) Environmental Monitoring: Myths and
Misapplications. PDA J Pharm Sci Tech. 55:176-184
6. Sandle, T. (2015b) Importance of Risk Assessment for a Aseptic Transfer in
Pharmaceutical Compounding, Clean Air and Containment Review, Issue 24, pp18-
23
7. Sandle, T. (2012a). Airflow visualisation in an aseptic facility, Cleanroom
Technology, 20 (5): 13-17
8. Sandle, T., Leavy, C. and Needham, G. (2012). A Risk Matrix Approach for Media
Simulation Trials,Journal of Validation Technology, 18 (4): 70-78
9. FDA (2004) Guidance for Industry Sterile Drug Products Produced by Aseptic
ProcessingCurrent Good Manufacturing Practice, U.S. Food and Drug
Administration, Rockville, MD, USA
10. Halls, N. (2004): Effects and causes of contamination in sterile manufacturing in
Hall, N. (Ed.):Microbiological Contamination Control in Pharmaceutical Clean
Rooms, CRC Press, Boca Raton, pp1-22
11. Whyte W and Eaton T. (2004a) Microbiological contamination models for use in risk
assessment during pharmaceutical production. European Journal of Parenteral and
Pharmaceutical Sciences 9 (1): 11-15
12. Whyte, W., and Eaton, T. (2004b) Microbial risk assessment in pharmaceutical
cleanrooms. European Journal of Parenteral and Pharmaceutical Sciences, 9 (1):
16-23
13. Sandle, T. (2012b): Sterility Test Failure Investigations, Journal of GxP Compliance,
16 (1): 1-10
14. Agalloco, J. and Akers, J. (2001) Validation of Aseptic Processing. In Swarbeck, J.
and Boylan, J. (Eds.) Encyclopedia of Pharmaceutical Technology, Marcel-Dekker,
New York, NY
15. Agalloco, J. and Gordon, B. (1987) Current Practices in the Use of Media Fills in the
Validation of Aseptic Processing, J. Parenteral Sci. Technol. 41 (4), 128141