Stockdale_pt_2 6/20/05 10:55 AM Page 1
ASEPTIC
Overview of Aseptic
Fill/Finish Manufacturing –
Part 2: Regulatory
Requirements
Douglas Stockdale
President, Stockdale Associates, Inc.
Article Overview
T
his is the second part of a three-part article series to provide a
broad overview of the aseptic fill/finish manufacturing process.
In the first part that was published in the September/October
2004 issue of this journal, I addressed the four principal systems that
define the aseptic fill/finish process: drug product, facilities & equip-
ment, sterile components, and personnel.
Part 1 of this article series had been prepared during the draft phase
of the new FDA Aseptic Guidance, and the FDA published the
Guidance while that article was going to print. Part 2 of this article
series will examine the New Guidance in more detail in the context of
the regulatory guidance for producing aseptic drugs.
The third article of this series will address the process validation of
aseptic processing and requirements of media simulations.
Introduction
In September of 2004, the FDA published its revised guidance on
the aseptic fill/finish of sterile drugs, titled Guidance for Industry:
Sterile Drug Products Produced by Aseptic Processing -- Current
Good Manufacturing Practice [1]. This replaces the FDA Aseptic
Guidance that had been published in 1987.
This new FDA Guidance had been provided to Industry for review
as a Draft document, and many comments were received from oper-
ating companies, individuals, and industry organizations. I am not
going to debate the merits of the recommendations to the Draft (well,
maybe in a couple of places) but to address what is now before us.
The FDA Aseptic Guidance is effective immediately, as it was
expressed by representatives from the FDA recently, that this is only
a Guidance to Industry.
The Regulatory Requirements
The vast majority of sterile drug products being produced are being
distributed globally, thus they are impacted by multiple Regulatory
requirements. The principal aseptic regulatory issue is that global
requirements are not fully harmonized. The difference in the
Regulatory requirements and how the requirements are interrupted
(read: enforced) also vary, thus a key reason for geographic sterile
drug manufacturing for regional distribution, e.g. USA, Europe, Asia.
This article was printed in the March/April 2005
1 issue of American Pharmaceutical Review.
Copyright Rests with the publisher. For more information about APR and to read similar articles,
American Pharmaceutical Review
visit www.americanpharmaceuticalreview.com and subscribe for free.
For the United States, the two FDA regulatory groups primarily
concerned with aseptic processing are the Center for Biologics
Evaluation and Research (CBER) and Center for Drug Evaluation
and Research (CDER). CBER had been focused on Biologics, which
included Biotechnology, and CDER was focused on Pharmaceuticals.
Within the last couple of years that differentiation has been blurred,
but for the manufacture of sterile drugs by aseptic processes, the same
Guidances are utilized.
For most of Europe, (EMEA) provides the regulatory overview for
aseptic processing, and utilizes the Annex 1 for Sterile Medicines. For
Japan, the Ministry of Health and Welfare (MHW) with the relative-
ly new Pharmaceutical & Medical Devices Evaluation Center
(PMDEC) is the principal regulatory agency.
For the other geographies of the world, they have their own indi-
vidual regulatory agencies; but, as a general rule, they will recognize
the regulatory requirements of ISO, FDA or EMEA.
New FDA Aseptic Guidance
I would like to first spend some time reviewing the new FDA
Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing --
Current Good Manufacturing Practice, published September 29, 2004 [1].
A brief summary of the changes to the 1987 Guidance:
The clean-room air designations now recognize ISO 14644, but the
terminology within the text of the Guidance still utilizes the class 100,
10,000 and 100,000. The ISO 14644 grade 5, 6, 7 & 8 only address
the particulate count regardless of where it is viable or non-viable in
nature.
The microbial requirements of the cleanroom are more harmonized
with the EU Annex 1 for the manufacturer of sterile medicines, but
there is no one-to-one harmonization of the cleanroom classifications
between the FDA Guidance and Annex 1. For example, the Annex 1
grade B cleanroom requirement for particulate is the same as class
100 without activity, but the same as class 10,000 during activity.
The “laminar” air process condition that was described in the 1987
Guidance now reflects a more accurate airflow condition called uni-
directional air flow. This change recognizes the large amount of doc-
umentation and data about airflow patterns that operating companies
Stockdale_pt_2 6/20/05 10:55 AM Page 2
ASEPTIC
have been generating with their smoke studies performed during
cleanroom and equipment qualifications.
The FDA Guidance is now further harmonized with Annex 1 with
the recommended room pressure differential to 10-15 Pascal (Pa).
The new FDA Aseptic Guidance recognizes current technology and
provides the opportunity to implement newer technology as it
becomes available. One of the current technologies that is identified
as improving the facility infrastructure for aseptic processing is the
availability of Building Management Systems (BMS). The utilization
of a BMS is to further automate the data collection and systemize
some action levels with the facility infrastructure of both the clean-
rooms and their supporting utilities.
Steam in Place (SIP), also identified as Sterilize in Place, is anoth-
er technology that is recognized as providing advantages to an asep-
tic process. SIP could provide the opportunity for closed aseptic pro-
cessing systems.
The FDA Aseptic Guidance also discusses sterilized bulk tank
requirements and other upstream aseptic processing and sterilization
requirements. The upstream sterile processes are now being required
to be included in the media simulations for process validation. Thus
if you are using good aseptic techniques to control bioburden, but you
do not have a requirement for sterility, I would not identify that as a
“sterile process” in your regulatory documents. Perhaps calling it a
“Bioburden Control Process” may be more appropriate, but then
again, that term may then open the Pandora’s box of “what are you
controlling it to?”
There are two annexes of the new Aseptic Guidance which address
the improved microbial control provided by Blow-Fill-Seal (BFS)
and Isolator technologies. Both of these technologies have extensive
publications documenting the reduced risk of microbial contamina-
tion when they have been successfully deployed.
With Isolator technology, the new Guidance does state that a “small-
er” quantity of media is filled for process validation, but we are left
to ponder what the vague value of “smaller” is.
New FDA Aseptic Guidance: Good Aseptic
Practices
It is my opinion that the success of an aseptic operation truly hinges
on the personnel who support and operation the system. Thus the
inclusion of good aseptic practices is very much appreciated, but I
caution you not to think that what is in the Guidance is totally inclu-
sive. Operating companies should develop their own good aseptic
practices procedures to be incorporated in cleanroom operator train-
ing and cleanroom conduct and then provide an annual training to the
cleanroom operational and support personnel.
Similarly, maintaining proper gown control and development of a
gowning qualification process is another best practice for good asep-
tic techniques that has been incorporated into the Guidance.
It has been my experience that the day-to-day operational clean-
room personnel do understand and maintain sterile techniques when
providing on-going training. A weakness with many sterile manufac-
turing facilities is the support personnel who do not routinely gown
and function in the cleanroom, especially when near or in the aseptic
core. I have found this especially true when support functions are
required outside the “normal” operation, as many small volume ster-
ile manufacturing operations are conducted during a “day” shift.
For maintenance support, one excellent resolution is to dedicate a
small maintenance team to the fill/finish operation who will exclu-
sively support cleanroom operations. A dedicated maintenance team
will sustain a sterile gowning qualification the same as the operational
personnel and maintain aseptic techniques in their workmanship. I
implemented this policy while I was an aseptic fill/finish manufactur-
ing manger, and I recommend it frequently as a consultant to my
clients. For most organizations, you only need to avoid one contami-
nated batch to have an immediate payback on your support personnel
investment.
This article was printed in the March/April 2005
2 issue of American Pharmaceutical Review.
Copyright Rests with the publisher.
American Pharmaceutical about
For more information
Review
visit www.americanpharmaceuticalreview.com and subscribe for free.
I have found that that by identifying each of the aseptic practices
that need to be considered by the cleanroom personnel, and
then including these in the sterile technique training, my clients have
seen an improvement in the their personnel to comply and meet the
identified aseptic techniques. The results have been documented in
the reduction of non-sterile technique observations by Quality
Assurance and Operational Management, as well as a reduction in
lot discrepancies.
New FDA Aseptic Guidance:
Environmental Monitoring
The new aseptic guidance has an extended section on environmen-
tal monitoring (EM). It discusses in greater detail the role of a micro-
biological laboratory in failure investigations and the significance of
a microbiologist for the support of an aseptic process.
Environmental monitoring and the use of nucleic-acid methods are
also discussed in the Guidance. The Guidance does open the door for
alternative EM methods that are currently being developed.
The new aseptic Guidance discusses EM data trending. From recent
discussions with those in the FDA and other published comments, I
am aware of the importance that the FDA is placing on this.
Environmental monitoring data is a key indicator of the cleanroom
operational conditions.
New FDA Aseptic Guidance: Process
Validation
The FDA Guidance does make new recommendations for the min-
imum quantity of containers filled during media simulations, which is
5,000 containers. The new Guidance also provides information on the
FDA’s expectations for media fill acceptance, which are no contami-
nations. I will address media simulations and process validation in
much more detail in my next article.
Chemistry, Manufacturing & Controls
(CMC)
The Chemistry, Manufacturing & Controls (CMC) section explains
aseptic drug manufacturing in your regulatory filing to the FDA. The
CMC section will be used during the drug development process, to
license your sterile product for commercial distribution, and will be
amended during the life of your drug license.
The CMC section would provide all of the details of your drug man-
ufacturing, from raw materials through upstream and finally down-
stream manufacturing. This section would identify all of the manu-
facturing steps that would require process validations. The process
validation protocols and summary reports would then be referenced
and submitted to the FDA as a section for the drug application.
There are a number of FDA CMC Guidance’s to provide you with
assistance. The primary Guideline for you to consider is the Content
and Format for the Chemistry, Manufacturing and Controls Section of
an Application.
This guidance will also provide help with understanding the require-
ments to amend or change your manufacturing processes. Regulatory
changes to the aseptic manufacturing of a licensed drug are similar to
other manufacturing changes: Annual reportable, Changes to be
Effected (also know as a CBE-30) or a Pre-Approval Submission
(a.k.a. PAS) which can lead to a Pre-Approval Inspection (a.k.a. PAI).
Briefly, the annual reportable changes are considered “minor” by
the agency and are provided to the agency on an annual schedule. The
CBE-30 changes have a requirement that they can not be implement-
ed for 30 days, during which the FDA will review and notify the com-
pany if additional information is required or the change is rejected. At
the conclusion of the 30 days, the company can implement the change
if it has not heard otherwise. Most companies will implement the
APR and to read similar articles,
Stockdale_pt_2 6/20/05 10:55 AM Page 3

ASEPTIC

change during the CBE-30 review and not release the product until
notification of the change acceptance.
The PAS is for major changes and, frequently for aseptic process-
ing, will also trigger the FDA to complete a PAI. Examples of a PAS
would be the expansion of the aseptic processing complex, new asep-
tic filling equipment or installation of additional sterile driers. Similar
to the CBE-30, the FDA has a time table to reject, accept or ask for
additional information, but within a six-month period of time.
Because of the critical nature of Aseptic Processing, manufacturing
changes can frequently become CBE-30’s and, if not carefully man-
aged, can quickly become PAS’s. The exception is the “like for like”
maintenance changes, and this too is an area of concern, as frequent-
ly the new “like” is not exactly the same as the old “like” that just
failed. Thus I recommend any change being effected in the aseptic
processing area to go through a diligent change control process, with
all decisions being well-documented.

Summary
The global regulatory landscape for aseptic processing is still evolv-
ing and from my perspective of over twenty years, evolving for the
better. Our processes are becoming more robust; we are working out
our differences with other countries regulatory agencies and arriving
at better harmonized requirements.

Reference
1. Guidance for Industry: Sterile Drug Products Produced by Aseptic
Processing -- Current Good Manufacturing Practice. September
29, 2004. http://www.fda.gov/cber/gdlns/steraseptic.pdf

Douglas Stockdale is the President of Stockdale Associates,

Inc., which provides extensive aseptic fill/finish and sterile
packaging consulting services for the life sciences industry. He
had twenty years of operational experience with Baxter
Healthcare prior to founding Stockdale Associates. He is an
internationally known expert consultant, speaker, and writer
about the issues of aseptic fill/finish and sterile packaging. His
company provides innovative strategic and implementation solu-
tions for product development, manufacturing, compliance/
auditing and validation.
He is a member of PDA, AAPS, IOPP & ISPE and a member
of the Board of Directors for the Greater Los Angeles chapter
of ISPE. Mr. Stockdale has a MBA from the University of La
Verne and a B.S. in Engineering from Michigan State University.

Correspondence should be addressed to:

Douglas Stockdale, President, Stockdale Associates, Inc.
Corporate Offices: 10 Reata, Rancho Santa Margarita, CA
92688, Phone: 949-888-9488, Fax: 949-888-1560
douglas@stockdale-inc.com or www.stockdale-inc.com

This article was printed in the March/April 2005

3 issue of American Pharmaceutical Review.
Copyright Rests with the publisher. For more information about APR and to read similar articles,
American Pharmaceutical Review
visit www.americanpharmaceuticalreview.com and subscribe for free.