ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE**
>
> Tuesday, October 22, 2002
>
> 8:30 a.m.
>
> Advisors and Consultants Staff Conference Room
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> PARTICIPANTS
>
> Vincent H.L. Lee, Chair
>
> Kathleen Reedy, Acting Executive Secretary
>
> MEMBERS
>
> Gloria Anderson, Ph.D. (Consumer Representative)
>
> Judy P. Boehlert, Ph.D.
>
> William J. Jusko, Ph.D.
>
> Joseph Bloom, Ph.D.
>
> Lemuel A. Moye, M.D., Ph.D.
>
> Marvin C. Meyer, Ph.D.
>
> Arthur H. Kibbe, Ph.D.
>
> Industry Guests
>
> Leon Shargel
>
> Efraim Shek
>
> Guests and Industry Participants
>
> Gerry Migliaccio
>
> Ken Lavin
>
> Michael S. Korczynski, Ph.D.
>
> Sandra A. Lowery, M.B.A., ASQ-CDA
>
> Anne Marie Dixon
>
> Berit Reinmuller, Ph.D.
>
> Don Burstyn, Ph.D.
>
> Jeanne Moldenhauer, Ph.D.
>
> Terry Munson
>
> Russ Madsen
>
> FDA Speakers
>
> Richard Friedman
>
> David Hussong
>
> Kris Evans
>
> Robert Sausville
>
> Brenda Uratani, Ph.D.
>
> FDA
>
> Douglas I. Ellsworth
>
> Jay Elterman
>
> Joseph Famulare
>
> Ajaz Hussain, Ph.D.
>
> Helen Winkle
>
> [C O N T E N T S]{.underline}
>
> Call to Order:
>
> Vincent H.L. Lee, Ph.D. 5
>
> Conflict of Interest:
>
> Kathleen Reedy 6
>
> **Future Subcommittee\--GMP Manufacturing**
>
> Introduction and Overview:
>
> Ajaz Hussain, Ph.D. 8
>
> Industry Perspective:
>
> Gerry Migliaccio 23
>
> Ken Lavin 29
>
> Committee Discussion 36
>
> **Manufacturing Issues**
>
> **Sterile Drug Products Produced by**
>
> **Aseptic Processing**
>
> Introduction:
>
> Ajaz Hussain Ph.D. 63
>
> Joseph Famulare 64
>
> Contamination Risk Factors:
>
> David Friedman 81
>
> Microbiology Review Perspective:
>
> David Hussong, Ph.D. 103
>
> Industry Perspective:
>
> Russ Madsen 108
>
> Design, Control and Contamination:
>
> Berit Reinmuller, Ph.D. 122
>
> **Open Public Hearing**
>
> Kenneth H. Muhvich, Ph.D. 135
>
> David J. Miner 137
>
> Professor Bengt Ljungqvist 144
>
> Martyn Becker 149
>
> Maurice Phelan 153
>
> Dimitri Wirchansky 157
>
> **Manufacturing Issues Discussion**
>
> Discussants: 168
>
> Sandra Lowery, M.B.A.
>
> Anne Marie Dixon
>
> Terry Munson
>
> Michael Korczynski, Ph.D.
>
> Don Burstyn, Ph.D.
>
> Jeanne Moldenhauer, Ph.D.
>
> Sterilization Options:
>
> Kris Evans 197
>
> Personnel:
>
> Robert Sausville 214
>
> [C O N T E N T S]{.underline} (Continued)
>
> **Manufacturing Issues Discussion**
>
> Environment Monitoring:
>
> Richard Friedman 227
>
> Media Fills:
>
> Brenda Uratani, Ph.D. 245
>
> Conclusion and Summary Remarks:
>
> Helen Winkle 290
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. LEE: Good morning. I am Victor Lee, Department of Pharmaceutical
> Sciences, School of Pharmacy at the University of Southern California
> in Los Angeles. I am the Chair of this Committee, the Committee for
> Pharmaceutical Science.
>
> Let me begin by asking the folks around the table to introduce
> themselves. Ajaz?
>
> DR. HUSSAIN: Ajaz Hussain, Deputy Direction, Office of Pharmaceutical
> Science.
>
> DR. MOYE: University of Texas, Biostatistics.
>
> DR. JUSKO: William Jusko, University of Buffalo.
>
> DR. MEYER: Marvin Meyer, Emeritus Professor, University of Tennessee.
>
> DR. KIBBE: Art Kibbe, Professor, Wilkes University.
>
> DR. ANDERSON: Gloria Anderson, Callaway Professor of Chemistry, Morris
> Brown College.
>
> DR. BLOOM: Joseph Bloom, University of Puerto Rico.
>
> DR. BOEHLERT: Judy Boehlert. I have my own pharmaceutical business.
>
> DR. SHARGEL: Leon Shargel, Eon Laboratories.
>
> DR. SHEK: Efraim Shek, Abbott Laboratories.
>
> MR. MIGLIACCIO: Gerry Migliaccio, Vice President of Global Operations
> from Pfizer representing PhRMA.
>
> MR. LAVIN: Ken Lavin, Director of Regulatory Compliance with Teva
> Pharmaceuticals representing GphA.
>
> DR. LEE: Thank you very much.  Kathleen, are you ready? We are kind of
> short-handed this morning. Kathleen is going to read us the
> conflict-of-interest statement.
>
> **Conflict of Interest**
>
> MS. REEDY: The following announcement addresses the issue of conflict
> of interest with respect to this meeting and is made a part of the
> record to preclude even the appearance of such at this meeting.
>
> The topics of today\'s meeting are issues of broad applicability.
> Unlike issues before a committee in which a particular product is
> discussed, issues of broader applicability involve many industry
> sponsors and academic institutions.
>
> All special government employees and federal guests have been screened
> for their financial interests as they may apply to the general topics
> at hand. Because they have reported interests in pharmaceutical
> companies, the Food and Drug Administration has granted waivers to the
> following special government employees which permits them to
> participate in today\'s discussions: William J. Jusko, Ph.D and Judy
> Boehlert, Ph.D.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A30 of the Parklawn Building
>
> Because general topics impact so many institutions, it is not prudent
> to recite all potential conflicts of interest as they apply to each
> member, consultant and guest. FDA acknowledges that there may be
> potential conflicts of interest, but because of the general nature of
> the discussion before the committee, these potential conflicts are
> mitigated.
>
> We would like to note for the record that Dr. Efraim Shek of Abbott
> Laboratories and Dr. Leon Shargel of Eon Labs are participating in
> this meeting as industry representatives acting on behalf of regulated
> industry. As such, they have not been screened for any conflicts of
> interest.
>
> DR. LEE: Thank you, Kathleen.
>
> I would like to begin the meeting by inviting Dr. Ajaz Hussain, Deputy
> Director of the OPS to give us the charge.
>
> **Future Subcommittee\--GMP/Manufacturing**
>
> **Introduction and Overview**
>
> DR. HUSSAIN: Good morning.
>
> \[Slide.\]
>
> I have prepared the presentation to talk about the Manufacturing
> Subcommittee that we proposed at a previous meeting and sort of lay
> out some details on that.
>
> I also have a backup set of slides that I thought I could use to spend
> a bit more time to give all of our other FDA colleagues to get
> together because of the incident this morning. So I think I can spend
> some time explaining this in a bit more detail than I had originally
> planned.
>
> \[Slide.\]
>
> At a previous meeting, we had proposed to you that we would like to
> create a subcommittee on pharmaceutical manufacturing and that the PAT
> subcommittee would essentially sunset as this complication sort of
> comes to become functioning.
>
> Just to give you a sense, manufacturing, pharmaceutical manufacturing,
> is addressed by different parts of the Agency as it is done
> differently in companies, too. So we essentially are looking at the
> quality system which includes how do we set specifications to the test
> and controls and falling GMPs and then, also including, from a quality
> perspective, making sure the specifications make sense, are linked to
> safety and efficacy and then, when there are changes, how do you
> manage to insure that the product performance is unchanged.
>
> So the quality system is quite a complex system with different parts
> of the Agency including a public standard-setting organization\--that
> is, USP\--that sort of comes to play in the overall quality system.
> So, if you start looking at it, how does each and every component work
> and how are these interlinked, I think it is time to take a hard look
> on that and see what improvements in the scientific foundation of this
> system can be done.
>
> \[Slide.\]
>
> So from the background perspective, pharmaceutical manufacturing is a
> very critical component of the industry and it has to function as
> efficiently as it can to make sure the quality products are available
> to the U.S. public.
>
> Manufacturing depends on R&D in developing optimal dosage forms. So I
> think the review part which we deal with, mostly R&D, has to set the
> specifications that are appropriate from a safety and efficacy
> perspective but also the specifications should be such that the
> manufacturability is considered appropriately.
>
> So you are looking at R&D and manufacturing as two big clumps within
> the industry and sort of, in reflection to that, you have the review
> and inspective clumps, and how do these function, I think, is an
> important goal of understanding this so that we can do a more
> efficient job.
>
> We started the PAT initiative about a year ago and that was with this
> in mind, how do you approve the science. That essentially has led to
> the new FDA initiative on cGMP for the 21st Century. So you have two
> major initiatives that are addressing pharmaceutical manufacturing in
> a global sense.
>
> \[Slide.\]
>
> The need for the Manufacturing Subcommittee was apparent to us even
> before we started the cGMP for the 21st Century initiative. So this
> Manufacturing Subcommittee we are proposing is to provide input and
> advice to CDER and FDA so manufacturing is not just Center for Drugs
> Review and Compliance, it is Office of Regulatory Affairs, and so
> forth. So this committee will have a much broader focus and input to
> the entire FDA in many senses.
>
> Our original plan was to use this Manufacturing Subcommittee to bring
> input to FDA on science-based CMC and GMP policies. But, keeping in
> mind the broader scope, and the sunset of the PAT Subcommittee, we
> would also like this committee to focus on providing input to us on
> continued development of the PAT initiative.
>
> Keep in mind, the PAT initiative with the subcommittee leads to a
> general guidance, but there will be need for many technical guidances
> that will have to be developed in this area and we will look to this
> committee for input on those issues.
>
> Clearly, the cGMP for the 21st Century, a risk-based approach, will
> benefit from a lot of the discussions that can occur at this
> subcommittee. So that is the thought process as to the scope of the
> subcommittee. It would range from very focused discussion on some
> topics. One example is the aseptic manufacturing discussion we have
> this afternoon to a broader discussion on other issues, too.
>
> \[Slide.\]
>
> We plan to model the Manufacturing Subcommittee after the PAT
> Subcommittee. It think the PAT Subcommittee was, in my mind, a very
> successful subcommittee that, with three meetings, gathered all the
> expertise and brought information to the FDA to help us write the
> draft guidance. Tomorrow is the last meeting, in once sense, of the
> PAT Subcommittee.
>
> What we have learned from that is if you identify the right
> individuals who have the scientific expertise, it really helps to sort
> of crystalize the process very well.
>
> Based on that sort of experience, what we are proposing is we will
> have a set of core membership, which is based on expertise in
> manufacturing and quality assurance to be part of this subcommittee.
> Some members of the PAT Subcommittee will be invited to participate as
> the PAT Subcommittee sunset, so you will have continuity built in.
>
> Then, once we have the core membership, we will have focused working
> groups or fact-finding groups which will sunset their activities after
> they have done their job. So this will be fluid working groups and
> fact-finding groups which will be assigned the task. Once they have
> completed it, they will sunset their activities and the entire group
> will focus on other areas.
>
> Since the cGMP for the 21st Century has many immediate steps outlined,
> initial topics that we may need to focus on under the subcommittee may
> be some selected immediate steps outlined in the cGMP for the 21st
> Century Concept Paper. That is one of the possibilities.
>
> \[Slide.\]
>
> Here what I thought I would do is take a step backward and sort of
> look at the 21st Century Concept Paper that we have distributed to you
> and share some more information about this initiative. There were many
> drivers that led to this initiative and what we have seen over the
> last two decades is increased numbers of pharmaceuticals and their
> greater role in healthcare. In fact, several years ago, the cost of
> drugs exceeded the cost of hospital care. So, the importance of
> medicines or drugs in healthcare is tremendous. At the same time, over
> the last decade, we have seen a decreased frequency of inspections.
> There are many reasons for that.
>
> Also, we have been accumulating our experience in lessons learned from
> various approaches to product quality but we have been doing that in
> segments. It is now time to take a step back and sort of look at the
> entire system and make sure the connections are there.
>
> Clearly, there have been advances in pharmaceutical scientific and
> manufacturing technology. Although we have brought some of these in on
> a step-by-step basis, it is again time to sort of look back and see
> how do we bring all of this into a complete system.
>
> Application of biotechnology not only for drug discovery but also for
> drug development and for manufacturing\--there are a lot of lessons to
> be learned from that. Clearly, there have been advancements in science
> and management of quality, itself. That revolution, the quality
> revolution, I think we can learn a lot from that. Clearly, we are
> looking at a global industry rather than just the U.S. industry,
> itself.
>
> \[Slide.\]
>
> The pharmaceutical cGMP for the 21st Century essentially describes
> that initiative as a science- and risk-based approach to
> product-quality regulation incorporating an integrated quality-systems
> approach. That is sort of the basic foundation of this initiative. It
> is intended to incorporate a more up-to-date concept of risk
> management and scientific advances, encourage innovation and
> continuous improvement, ensure that submission review and cGMP
> inspection are coordinated and are synergistic and also ensure we have
> consistency and effective utilization of our resources.
>
> So, in many ways, when you look at the title, the title is a bit
> narrow and I think the scope of this\--in my mind, the correct title
> would be a drug-quality system for the 21st Century instead of cGMP.
> It is an entire system that we are looking at.
>
> \[Slide.\]
>
> The guiding principles that we have developed for this initiative are
> several. We will have a risk-based orientation, science-based policies
> and standards, integrated quality-system orientation, international
> cooperation. Clearly, the strong public-health protection is always
> the foundation on which we will base all this on.
>
> \[Slide.\]
>
> We have outlined several steps. We are in the process of performing an
> external review of our existing cGMP programs and product-review
> practices including evaluation of potential inconsistencies in the
> implementation, reassess and revaluate our scientific approach to both
> the product-review process and cGMP program to achieve a consistent
> integrated-systems approach to product-quality regulation, enhance the
> scientific approach of cGMPs to emphasize risk-based control-point
> analysis and to facilitate the latest innovation in pharmaceutical
> engineering.
>
> Those are the sort of broad steps that we have outlined.
>
> \[Slide.\]
>
> We have set for ourselves some immediate steps. An immediate step
> means we would have some results within six months. February is the
> deadline we are looking at. It doesn\'t mean we will implement all
> that. We will have developed our understanding and our plans to a
> degree that we can actually start presenting some of these immediate
> steps to the stakeholders.
>
> Among the immediate steps which I think will be the focus of some of
> our discussions in the subcommittee, holding scientific workshops with
> key stakeholders, enhancing expertise in pharmaceutical technology;
> for example, pharmaceutical engineering and industrial pharmacy by
> additional training and hiring and by leveraging external expertise,
> encouraging innovation within the existing framework by allowing
> certain changes in manufacturing processes without prior review or
> approval; for example, use of comparability protocols.
>
> So I believe those are the main topics that we might start out in the
> subcommittee.
>
> \[Slide.\]
>
> But, there are other steps which may not be directly linked to the
> subcommittee activities which may include evaluating the optimal
> mechanism for effectively and efficiently communicating deficiencies
> to industry including content, consistency, disclosure and education;
> shifting the Agency lead on implementation of Part 11 to CDER\--that
> has already occurred\--with continued involvement from other centers
> in ORA; including product specialists as needed as part of the
> inspection team
>
> \[Slide.\]
>
> Having centers provide a scientific and technical review of all drug
> cGMP warning letters; developing a technical dispute-resolution
> process that integrates technical experts from the Centers and
> addresses perceived inconsistencies between Centers; emphasizing a
> risk-based approach in the work-planning process and improving the
> operation of Team Biologics.
>
> \[Slide.\]
>
> The way we are moving forward is we essentially have created a set of
> working groups and a GMP Steering Committee. This is just to show the
> number of working groups active that are focused on the initial
> short-term milestone which is six months or less. We have a group on
> Contract Management, International Activities, Part 11, Dispute
> Resolution, Warning Letter Review, 483 Communications, Changes without
> Prior Review, Product Specialists on Inspection Team, Working Planning
> and Risk Management, Cadre of Investigators, Developing Science
> Aspect, Evaluation of the Initiative, itself, and Quality Systems.
>
> We have not started working on a Training Program at this time.
>
> \[Slide.\]
>
> SO, with that sort of a backdrop, I just wanted to share some thoughts
> on what the Manufacturing Subcommittee might take up as initial
> topics. Potential discussion topics, as examples, could include, I
> think, starting with Definitions and Common Understanding. What do we
> mean by a risk-based approach in the context of manufacturing. I think
> we would need to start discussing and sort of building a common
> consensus on what does risk constitute or in the context of
> manufacturing, what does that mean?
>
> What do we mean by an integrated-systems approach? What is meant by a
> science-based approach? We have always been a science-based agency but
> what is different now? Science of quality? What is that and what is
> modern quality thinking, and so forth?
>
> So these are some examples of the words we use but which may have
> different meaning to different individuals and we need to have some
> common understanding.
>
> \[Slide.\]
>
> Just to give you sort of my way of looking at some of these words, if
> I go to Webster and pick up the definitions which I think apply.
> First, art; the power of performing certain actions, especially as
> acquired by experience, study or observations.
>
> What does empirical mean; relying on experience or observation alone
> often without due regard for system and theory. What is science;
> accumulated and accepted knowledge that has been systematized and
> formulated with reference to the discovery of general truths of the
> operation of general laws.
>
> \[Slide.\]
>
> What is a system: a regularly interacting or interdependent group of
> items forming a unified whole; an organized set of doctrines, ideas or
> principles usually intended to explain the arrangements or working of
> the systematic whole marked by thoroughness and regulatory. What do we
> mean by risk; risk is the possibility of loss of injury but also the
> degree of probability of such loss.
>
> Clearly, I think we have to distinguish between possibility and
> probability and how do we sort of bring that into focus.
>
> \[Slide.\]
>
> But, at the heart of the whole debate, I think, what is quality and
> what is modern quality thinking? Here is some sense of that from eight
> quality gurus who have tried to define quality.
>
> At the first level, quality is producing products or delivering
> services whose measurably characteristics satisfy a fixed set of
> specifications that are usually numerically defined. That is what
> quality is.
>
> But, at level 2 it is customer satisfaction. In the modern way of
> thinking in terms of risk, I tend to look at FDA\'s role in this arena
> as a surrogate customer for our patients. We are the surrogate
> customers that have to be\--I think satisfying our expectations leads
> to sort of a risk reduction and so forth. So that would be the sort of
> debate and discussion that we could have.
>
> \[Slide.\]
>
> More specific examples of topics that can be brought to this committee
> include approaches for enhancing the scientific basis of regulatory
> policies. We can pick topics and have focused discussion and this
> afternoon, I believe, would be one such example.
>
> Regulatory approaches regarding aseptic manufacturing; I think our
> goal here is to ensure a sound scientific basis for cGMP inspection
> practices. The discussion this afternoon will be lead by our GMP
> colleagues. We haven\'t seen Joe yet\--oh; Joe is here. I was trying
> to drag on, Joe, to make sure you were here. Joe Famulare will take
> the lead on the discussion and sort of bring to you their perspective
> on what are the important aspects here. I am hoping you would give
> them feedback in terms of how do you focus on science and making sure
> it is sound scientific basis and not simply going through a process
> where we have a \"check box\" exercise.
>
> Science-based risk assessment and management, and so forth. But, also,
> I think, one opportunity here is to bring controversial topics such as
> general unresolved scientific technical disputes between industry and
> FDA. This would be different from dispute resolution on a
> company-by-company basis but sort of bring more general issues here.
>
> \[Slide.\]
>
> What I would like to do; we have invited two guests, Gerry Migliaccio,
> who will represent PhRMA and Ken Lavin will represent GphA. After you
> listen to their perspective, if you could give us some input on what
> our goals and objectives of the subcommittee should be, the process
> that we have proposed\--that is, have a core member group, two members
> from this advisory committee, maybe eight to ten expert participants
> representing stakeholders and then use the concept of fact-finding
> groups or working groups and how would we evaluate the success of this
> subcommittee.
>
> So I will invite Gerry Migliaccio to sort of share PhRMA\'s
> perspective and then the GphA perspective and then your thoughts.
>
> Thanks.
>
> **Industry Perspective**
>
> **PhRMA**
>
> MR. MIGLIACCIO: Good morning. Thanks, Ajaz. I would like to thank the
> committee for inviting me to represent PhRMA to discuss to proposed
> Manufacturing Subcommittee. I won\'t be using slides because they
> would probably be identical to Ajaz\'s. We have run into this at many
> meetings recently.
>
> But PhRMA is extremely optimistic about the FDA\'s GMP initiative
> which Ajaz had just outlined. It is a positive step forward in the
> creation of what we have been advocating which is science-based GMP
> standards. It allows both FDA and industry to refocus their GMP
> compliance activities on what is important for fitness for use of the
> product. So, in other words, it allows us to focus our efforts on the
> patient.
>
> This committee has been instrumental in promoting process analytical
> technology. That technology and other innovative technologies that are
> emerging in the pharmaceutical-manufacturing business have the
> potential to provide us with significantly more knowledge about the
> products and processes that we produce and that we use and have the
> potential to enhance quality assurance.
>
> Now, if you combine those innovative technologies with science-based
> GMP standards, we truly have revolutionary potential in quality
> assurance in this industry. But, as in any case when you have
> revolutionary potential, it needs to be harnessed, it needs to be
> guided properly.
>
> I believe that this Manufacturing Subcommittee can play a significant
> role in guiding efforts around the GMP aspects, particularly the
> science-based GMP standard aspects of this initiative.
>
> In particular, I believe it will allow both FDA and industry to
> leverage their resources and to focus them on those things, again,
> that are critical to the fitness for use of our products.
>
> There are four specific areas where I think the subcommittee can make
> a significant impact on the GMP initiative. The first area; there will
> be many opinions about what is most critical in the area of
> science-based standards. From a PhRMA perspective, we believe that
> aseptic-manufacturing practices are crying out for science-based
> guidance.
>
> Other people will have different opinions. This Manufacturing
> Subcommittee should serve as the steering committee to identify what
> the most important areas are for science-based standards and to
> prioritize the work on those. Whether that work is to done at PQRI or
> elsewhere, someone will need to prioritize that work and I believe
> that Manufacturing Subcommittee is the right place for that to be
> done.
>
> Secondly, as Ajaz talked about risk and risk-based approach, there are
> going to be many views. There are many views today on what risk-based
> means, both risk-based GMP compliance and risk-based CMC review. The
> subcommittee can provide the manufacturing and the quality-assurance
> perspective on risk-based in the context of those two, the GMP
> compliance arena and the CMC review.
>
> Again, there will be many other perspectives on that. The common
> denominator to all those perspectives, again, is fitness for use. But
> I believe that this subcommittee can perform an important role in
> bringing together the perspectives of the manufacturing community and
> the quality community on what mean by risk-based.
>
> The third area, which is\--again, Ajaz talked about dispute
> resolution, what we are mostly calling technical-issues resolution;
> the subcommittee can play a significant role in the technical-issues
> resolution process that FDA is currently developing, not as the key
> player in resolving the issues between a firm and the FDA. There needs
> to be an entire process developed for that.
>
> But, just as in pharmaceutical manufacturing, you cannot address a
> problem or a deviation on its own. Yes; you deal with that deviation
> but then you have to step back periodically and do a trend analysis
> where the recurring issues that are cropping up not just in that area
> but industrywide. So not just with one firm but what is cropping up on
> an industrywide basis, what are the common issues that we are seeing
> come into this technical-issues resolution process.
>
> In the early stages of the GMP initiative, the subcommittee evaluating
> trending what is happening in the technical-issues resolution process
> is going to identify the need for science-based standards. As we move
> on and mature in our science-based GMP standards, the trending of what
> is happening in the technical-issues resolution process will allow the
> subcommittee to clarify standards, to modify standards as required to
> meet the needs of what is occurring out there. So I think there is a
> significant role in that process for the manufacturing subcommittee.
>
> Finally, the subcommittee should continue the work, really the model,
> that has been set by the Process Analytical Technology Subcommittee.
> It should serve as the vehicle for the introduction of new
> technologies in the pharmaceutical manufacturing sector.
>
> There are perceived hurdles. There are perceived regulatory hurdles to
> introducing new technologies in pharmaceutical manufacturing. Some of
> those hurdles are valid. Some of them are not. But what there is not
> today is a forum for addressing new technologies on an industry-wide
> basis and on an agency-wide basis. The Manufacturing Subcommittee can
> serve as that forum to evaluate and enable.
>
> The FDA has strongly stated that they do want to enable the
> introduction of new technologies and this Manufacturing Subcommittee
> can ensure that they are enabled.
>
> This subcommittee has to have the appropriate expertise to achieve
> those four roles that I believe it should play. It should have,
> obviously, the best minds of FDA in this arena but it should also have
> a broad base of industry representation to ensure that all
> perspectives are heard and are provided to the debate.
>
> Representatives from innovator firms in the traditional drug-product
> sector, the biotechnology sector as well as in the
> active-pharmaceutical-ingredients sector should participate in this
> endeavor. PhRMA members stand ready to serve on the committee and we
> are very supportive of its mission, and we highly endorse the
> proposal.
>
> Thank you.
>
> DR. LEE: Thank you very much.
>
> Are there any questions? If not, we have Ken Lavin to speak about the
> GphA Perspective.
>
> **Industry Perspective**
>
> **GphA**
>
> MR. LAVIN: Thank you and good morning. On behalf of the GphA, I would
> like to thank you for allowing me to speak to you regarding this
> important initiative to enhance the GMP. We believe this program is an
> important step in clarifying industry\'s requirements in providing
> safe, effective as well as affordable pharmaceutical products to the
> American public.
>
> \[Slide.\]
>
> We currently believe there exists a wide array of opinions and actions
> on the part of the Center and the field on various GMP topics. These
> opinions and actions also vary from district to district. It is costly
> for firms to be constantly addressing divergent thinking on these
> items. One voice and one set of actions by the FDA would further the
> ability of our companies to address the concerns of the agency.
>
> Inconsistency in inspection and review has let firms to make the most
> conservative decisions and these may not necessarily be the best
> decision. This thinking is also limiting to our abilities to add and
> utilize technologies.
>
> To ensure consistent interpretation and utilization, we believe that
> the publication of guidance documents will enhance overall compliance
> and provide clear direction to the industry.
>
> \[Slide.\]
>
> Some of the areas or topics that we feel should be discussed and the
> proper guidance provided for are, but not limited to, cleaning
> validation, process validation, training and vendor qualification.
>
> \[Slide.\]
>
> Cleaning validation; what is the level of cleanliness desired?
> Clarification and true guidance on the use of the matrix approach to
> cleaning validation is needed. Technologies exist that can monitor and
> ensure a clean until clean approach. This approach is currently
> frowned upon. Firms cannot possibly address all the concerns of the
> Agency without clear guidance on this topic.
>
> In light of the PAT initiative, we urge the FDA to consider this topic
> in a review of the currently Cleaning Validation Inspection Guidance.
>
> \[Slide.\]
>
> Process validation; currently firms expend a great deal of time and
> expense validating their processes. We feel that, while validation is
> necessary, the information gleaned from these programs could and
> should be used to lessen the burden on future manufacturing.
>
> This information could lessen our in-process testing regimen. Further,
> validated process should allow a firm to eliminate unnecessary testing
> such as blend-uniformity testing.
>
> \[Slide.\]
>
> Personnel and the training they receive dictate the outcome of many
> processes. We believe that the defining document describing the
> requirements for training and the documentation and tracking of the
> training all personnel receive is needed. Further clarification on
> these topics will enhance our abilities to provide the pertinent and
> up-to-day training our employees require.
>
> Vendor qualification; our vendors of active and inactive ingredients
> provide us with the materials we need to manufacture quality products.
> These suppliers are also subject to the same regulatory and
> inspectional requirements as the finished dosage for manufacturers.
>
> We believe that a guidance document on the qualification of these
> vendors that allows us to use these supplies and materials with a
> reduced testing program is warranted. This will allow us to use these
> materials without adding costs when the majority of the tests needed
> to release this materials for use have already been performed by
> qualified manufacturers.
>
> By providing industry with the guidance documents, we believe that the
> goal of protecting the American public in providing safe, pure and
> effective products is assured. Industry cooperation and input into
> these guidance documents is paramount to the success of this program.
> Inspection and review based on these documents will provide consistent
> compliance and provide our industry with the needed information to
> provide these products.
>
> \[Slide.\]
>
> The GphA looks forward to continued dialogue on these subjects and
> supports the endeavor of providing these guidances. We do have members
> that will sit on any subcommittee as needed.
>
> Thank you.
>
> DR. LEE: Thank you very much. Any immediate questions?
>
> DR. HUSSAIN: I want to introduce Doug Ellsworth who is the District
> Director from the New Jersey District and Joe Famulare who is the
> Director of Regional Manufacturing and Product Quality.
>
> DR. MOYE: I believe I understand what vendor qualification is and
> training. Process validation, I probably need some help on, but I can
> figure that out. But I don\'t know at all what cleaning validation is.
> Can you tell me what that is, please?
>
> MR. LAVIN: Would you like me to answer that?
>
> DR. MOYE: Please.
>
> MR. LAVIN: Cleaning validation is assuring that any material that
> remains from a previous product and equipment is removed prior to
> introducing new materials into that equipment. That is done by
> swabbing or rinsing and then testing the rinse aid or the swabs for
> the presence of the previous materials.
>
> DR. MOYE: Just to further parade my ignorance, there is no
> acknowledged industry standard for that; is that right?
>
> LAVIN: No; there is not. There exists a guidance to inspections on
> cleaning that gives vague references to 10 parts per million or one
> one-thousandth of a dosage unit, but there are many interpretations by
> different firms as well as different investigators on what exactly is
> cleaning.
>
> DR. MOYE: So there is guidance.
>
> LAVIN: Well, there is not really. There are suggestions to guidance.
> It is not really a guidance document. It is a guide to inspections. It
> is an FDA internal\--
>
> DR. MOYE: I see. So there is not even guidance.
>
> MR. ELLSWORTH: No.
>
> DR. MOYE: When the FDA carries out its inspections, does it find wide
> variability in cleaning either procedures or cleaning goals? There is
> no common calibration for cleaning?
>
> MR. FAMULARE: That\'s correct.
>
> DR. MOYE: Thank you.
>
> MR. FAMULARE: This is an observation that comes up from time to time
> and there are variations from company to company. I don\'t have any
> statistical answer to give you that X number of companies have X
> number of problems, but it does run the gamut from trying to get down
> to certain parts per million when going from one process to the other
> to the extreme where we find API facilities that are manufacturing
> chemical materials on the same processing equipment as APIs that are
> intended for human use.
>
> So there is an extreme of findings there.
>
> DR. LEE: Any other questions before we go into the committee
> discussion?
>
> MR. ELLSWORTH: One comment I would like to make in terms of
> cleaning-validation guidance. There are inspection guides, but I think
> it comes down to the science of how clean is clean. I know there are a
> number of publications that use different criteria but I think, for
> investigators in the field, looking at that is whatever scientific
> justification the term has.
>
> I don\'t know if FDA has specific, or doesn\'t have a specific
> guidance on what should be followed in terms of how clean is clean.
>
> DR. LEE: I think we will come to that later on this morning.
>
> **Committee Discussion**
>
> DR. LEE: OPS has posed a number of questions for the committee to
> discuss. I wonder whether we can put this up on the screen again.
>
> \[Slide.\]
>
> Those are the questions, the goals and objectives, the process and
> evaluation.
>
> Art, you have been very quiet this morning.
>
> DR. KIBBE: Thank you, Vince. Am I supposed to have an opinion?
>
> DR. LEE: Yes. You always have an opinion.
>
> DR. KIBBE: I had a question for Ajaz. I was going to catch him
> afterwards, but, since you put me on the spot. On your third immediate
> step, it says here, \"Having Centers provide a scientific and
> technology review of all drug cGMP warning letters.\" What does that
> really mean?
>
> DR. HUSSAIN: It is a process that we are looking at in terms of
> issuance of warning letters, having Center input into that more so
> than we do now.
>
> MR. FAMULARE: I think the real difference in that is, back in 1990,
> when warning letters began as an entity, they took over from
> regulatory letters. All regulatory letters were reviewed by a
> Headquarters unit, whether it be CBER, CDER, CVM. When we want to the
> warning letter, one of the issues about the issuance of the letters
> was the efficiency in time and processing them.
>
> We found that it very often took so much time before the letter went
> through so many levels of review that it wasn\'t timely. So, direct
> reference was given to field officers such as Doug Ellsworth\'s New
> Jersey District and the nineteen other districts to issue warning
> letters on GMP deficiencies for dosage-form products.
>
> There are some other examples, but that is the primary one. What the
> GMP for the 21st Century is looking at is to\--actually, a decision
> has been made to bring those letters back into Headquarters for
> technical review, review for consistency. The process is ongoing now
> to look at doing that and to have the proper resources in place.
>
> DR. KIBBE: When I read it, I was concerned about going back to the
> situation where it took seven years to get a warning letter out on\--I
> am exaggerating, of course. The understanding I had about warning
> letters is it was a way of getting the industry to recognize that
> there was a problem and to get it fixed quickly to minimize the time
> between an inspector recognizing the possibility of a problem that
> might impact quality and the industry responding to it so that that
> window was narrow.
>
> When I read this, I started thinking about that window getting wide
> again.
>
> MR. FAMULARE: Exactly. We are aware of the balance that we have to
> strike there to make sure that we get them out quickly. We have to put
> a system in place that, if we are going to have Headquarters review,
> we have to do it in a way that they are done quickly or we will not be
> able to be effective with them.
>
> But the idea of bringing them into Headquarters review is, again, to
> promote consistency and technically correct GMP points. That is not to
> say that all warning letters have those issues, but issues have been
> brought to light in terms of what one district says versus this other.
> So we are looking at it from that standpoint.
>
> DR. KIBBE: Just a small aside. I think it is admirable to try to get
> warning letters as correct as possible before they go out. I would
> encourage that the Center people spend time educating the inspectors
> in a way that they share information so that they become comfortable
> with allowing the inspectors and the field people go to ahead and
> continue to issue warning letters.
>
> I think we are better served, in a way, to push authority down if we
> have confidence in the people we are sending out in the field. It kind
> of sends the message that the Centers aren\'t confident that the
> people who are doing the inspections can do a quality inspection and
> send out a quality letter.
>
> Do you know what I mean?
>
> MR. FAMULARE: I wouldn\'t take it as a lack of confidence in the
> field. The important thing is to be able to have proper airing for
> those difficult or highly technical issues that sometimes need
> additional input. We want to be able to have the opportunity to
> provide that.
>
> Doug can address, at the field level, how important it is to get that
> level of confidence as well with continued hiring and so forth.
>
> ELLSWORTH: I think the issues relating to the warning letter, it is a
> bigger issue and we are working on improving the communication between
> technical experts that may be in the Center or elsewhere and the field
> so that we do have even stronger consistency in our inspectional
> process even before we get to that warning-letter stage.
>
> DR. LEE: Let me bring the discussion back to the charge to this
> committee which is to discuss the goals and objectives. I would like
> to remind the committee that this subcommittee is patterned after the
> PAT Subcommittee which is now being sunset.
>
> Those of us who were here yesterday and heard the presentation and, at
> least from our perspectives, the PAT Subcommittee seems to work quite
> well. I would like read the slide that Ajaz showed. It is about the
> science and risk-based approach to product-quality regulation in
> cooperating an integrated quality-systems approach.
>
> I just want to hear from the committee how you feel about the goals
> and objectives. Do you have any strong opinions, any advice? Yes,
> Leon?
>
> MR. SHARGEL: I am in full agreement that the subcommittee is a good
> idea and science-based guidances and approaches to GMPs is
> appropriate. I would like the subcommittee to consider something that
> Mr. Lavin brought up, the level of testing.
>
> In my experience, it is easier to add tests in the field than to take
> away a test, and to be examining what tests are really necessary. Are
> we testing too much or are we testing in the right places. As this is
> evolving, what is the most appropriate way of reaching good-quality
> products in manufacturing.
>
> DR. LEE: Thank you.
>
> Judy?
>
> DR. BOEHLERT: I would also like to add my support to the concept. I
> think we heard from DPHA and PhRMA that there is a need for guidance
> documents. Although they had different areas that they were focussing
> on, one on process validation, cleaning validation, the other on PAT
> and aseptic processing.
>
> Clearly, the need exists. I think the challenge for the committee is
> going to be to gain consensus on some of those issues because there is
> a dichotomy between those that want a lot of guidance and those who
> want to be told what to do but not necessarily how to do it. So that
> will be a real challenge for the committee.
>
> The other challenge I see is being able to include all the stakeholder
> groups that you might want. You have generic manufacturers. You have
> pioneer manufacturers. You have development companies. You have API
> manufacturers. You have drug-product manufacturers, whether they are
> conventional or sterile products. You have a lot of different
> audiences out there.
>
> You have the biotech industry and can you get all the right people
> together in the same room and yet limit the number of attendees so you
> don\'t have a huge committee. So there are going to be some
> challenges. However, I do support the concept very strongly.
>
> DR. LEE: Efraim?
>
> SHEK: I would like to add a little bit of international flavor to it.
> In your background, Ajaz, you talk about the international
> cooperation. We know we have the ICH, of course, going on. But I
> believe it would be very nice if this subcommittee will have also this
> aspect. As with their guidance or regulations, science-based are being
> implemented, that the aspect of international harmonization should be
> taken into account as many of the companies are becoming global.
>
> The world get smaller. It will be extremely helpful.
>
> DR. LEE: Thank you.
>
> Gloria? Gloria, by the way, is the consumer representative.
>
> DR. ANDERSON: I have been looking through these papers I have here and
> I can\'t seem to find the statement of goals and objectives. Can you
> tell me where that is?
>
> DR. HUSSAIN: The slide No. 4 was essentially the broad goals that sort
> of we proposed. Our initial thoughts were to use this committee to
> have input and advice to CDER FDA on science-based CMC and GMP policy
> development in the manufacturing area. That is the sort core long-term
> aspect, but also continue development of the PAT initiative. Then, at
> least for certain aspects of the cGMP for the 21st Century initiative,
> itself.
>
> So those are the three broad areas. I didn\'t call those goals but I
> think addressing, providing scientific input in those three areas are
> the goals.
>
> DR. ANDERSON: I would expect the objectives to be a bit more specific.
> It is difficult for me to comment on them when I don\'t quite see
> them. I know what they are for the PAT committee and I think it is
> commendable that you are going to continue that. But it would be
> helpful to me if I knew a little bit more about specific detail
> regarding the objectives.
>
> DR. HUSSAIN: If I may, I did not specifically identify that, but in
> terms of a bit more specifics, some of the topics for discussion, in
> my mind, one of the first topics was definitions and sort of common
> understanding of the terminology, the risk-based approach, what do we
> mean by risk-based approach in the manufacturing context.
>
> I think we have different perspectives but don\'t have a common
> understanding. So maybe one of the first topics we might pick up is
> defining these terminologies from different perspectives and sort of
> moving forward from there. That was sort of one objective, was clarity
> and definition.
>
> The other objectives that I laid out in my presentation, itself, to
> start focusing on topics, approaches for enhancing the scientific
> basis for regulatory policies. An example that this afternoon we will
> start with that process is the aseptic manufacturing process, itself.
> So it is sort of staged.
>
> We start out with maybe the fundamental basic definitions and then get
> into detailed topics for discussion. For those topics, we may need to
> bring a focused working group because the general, or the core
> membership of the subcommittee may not be the entire\--have the
> expertise in all given areas.
>
> So that is how we laid that out.
>
> DR. LEE: May I turn the question back to you? What do you think ought
> to be the objectives?
>
> DR. ANDERSON: I don\'t think I am in a position to do that. I think
> somewhere in the document that you have you have defined a problem and
> out of that would grow the goals of the committee with some specifics
> as to how you would achieve those goals.
>
> I usually look at goals and objectives in terms of what I hope to have
> accomplished at the end of whatever task I am doing. Of course, in my
> three years on this committee, it seems as if we have never gotten to
> the end of anything so that may be kind of difficult.
>
> But I don\'t have any specifics other than those that relate to PAT
> which I am familiar with. I would be willing to talk with you about
> them rather than prolong this discussion.
>
> DR. HUSSAIN: Many times, what we do is, for example, we came to
> fruition yesterday on blend uniformity. Essentially, that topic is
> completed. We discussed it twice at the advisory committee. The next
> step is guidance. So most of our end result generally is gathering
> information and then leading to a guidance document.
>
> So, in the duration of, say, the last three years, if you look at\--we
> finished the guidance on food effects. We finished the guidance on
> BA/BE. We essentially finished the discussion on blend uniformity. We
> finished the discussion on polymorphism. So, in many ways, all these
> were completed projects.
>
> DR. MEYER: In a sense, Ajaz, I am sure your immediate and intermediate
> steps are sort of the objectives of the committee.
>
> DR. LEE: Would Gerry and Ken care to comment on the goals and
> objectives, what you would like to see as the goals and objectives of
> the committee?
>
> MR. MIGLIACCIO: The four points that I put up are, certainly, from a
> PhRMA perspective what we would like to see the initial objectives of
> that committee. Again, to identify and prioritize the areas that
> require science-based GMP standards, to provide the manufacturing and
> quality perspectives on risk-based which, as Ajaz has pointed out, is
> something that needs definition.
>
> Thirdly, to be involved in the technical issues resolution process as
> in a trend analysis capacity in a clarification of standards. Then,
> finally, to continue with the PAT model and focus on new technologies.
> So I think those are four key objectives for the committee.
>
> LAVIN: I think what really should come out is a consensus type of
> document developed by FDA and industry on what are the risks, what are
> the associated risks and what can we do to mitigate those risks. Our
> businesses are not in business to be noncompliant. That is not what
> our objectives are.
>
> The FDA does not want that. We don\'t want that. As an American
> citizen and a consumer of those products, I don\'t want that. What we
> need is a clear set of directives or at least an open dialogue so that
> we can discuss these things instead of a hit-and-miss approach amongst
> firms, amongst districts, amongst investigators as well as between the
> districts and the Centers, themselves.
>
> It is very confusing. Most have a handle on it. Most companies are
> dealing with that. But, just to be consistent in the approaches and
> what are the risks and mitigating those risks I think will go a long
> way to protect the American public.
>
> DR. LEE: Well said. It seems to me the two words that cut across every
> area is the science and public-health protection. Science, as you
> know, always moves forward and, therefore, that is the standard is to
> move in pace with that.
>
> So I think the goals and objectives are things still evolving that we
> kind of know in our mind what they could be and I just don\'t think
> that we have the time to articulate precisely what those look like. So
> maybe that would be the first charge to this subcommittee is to
> clarify the goals and objectives for it. I think that we kind of have
> sufficient input.
>
> Is there any other discussion?
>
> DR. HUSSAIN: Two points. I think Judy raised a very important issue is
> the membership and representation. It is a very wide-ranging set of
> stakeholders and how do we manage that process. Efraim also raised an
> issue which I think is very important which is international
> cooperation. My experience with the PAT has been, because of the
> international membership on that group, in many ways, I think we have
> achieved harmonization without even talking about the harmonization
> process.
>
> The reason is I think the science evolved incorporating the
> perspective from both sides of the Atlantic. So I think that is also a
> lesson learned and how do we capture that in this if we can.
>
> DR. LEE: Very well. This is a proposal on the screen, two ACPS
> members. That is it on this side of the table. And eight to ten expert
> members representing the stakeholders. Any comments about that?
>
> DR. MEYER: Will FDA be represented, the A stakeholder, or\--
>
> DR. HUSSAIN: No; we don\'t count ourselves as part. We are here to
> listen and seek advice so we are not in one of those numbers there.
>
> DR. MEYER: Who selects the working groups? These are, I assume,
> largely in addition to the eight to ten experts?
>
> DR. HUSSAIN: We have some flexibility and we have different processes
> that we can do this. A subcommittee or a fact-finding group, we can
> actually appoint and select on our own. We don\'t have to go through a
> formal Federal Register process for that.
>
> But, in the PAT subcommittee, what we had done was we had announced in
> the Federal Register a request for\--we defined expertise and we
> invited people to participate. We had a very large number of
> applications that came in. So what we did in that case was select a
> core group and then we invited others who had applied to be a part of
> the different working groups. That is how we had done that. But we
> don\'t have to have that restrictive process.
>
> Kathy, do you want to say something?
>
> MS. REEDY: The working groups are very flexible. The subcommittees are
> less so. Two members from the core committee is really the only
> requirement.
>
> DR. KIBBE: That is a minimum; right?
>
> MS. REEDY: Yes.
>
> DR. LEE: I would like to follow up on what Marv said, whether or not
> there ought to be representation from the agency as some kind of a
> staff liaison.
>
> DR. HUSSAIN: Could you repeat that?
>
> DR. LEE: I think, in some organizations, you always have, let\'s
> say\--let me point out the organization I know a little bit about is
> AAPS. There are a number of committees and each committee is supported
> by a staff member who is a resource. So that person is going to go get
> the information, get things done, that sort of thing.
>
> DR. HUSSAIN: What we plan to do is we don\'t want to burden our
> Advisors and Consultants staff to that degree. So, what we have tried
> to do is try to help them\--actually, with the PAT groups and so
> forth, OPS has been providing some logistic support also so we will
> try to do the same thing. I think the Advisors and Consultants staffs
> are doing such a good job already, but their resources are limited. So
> we will have some other liaisons identified.
>
> Marilyn is a liaison from OPS for this committee. We will create
> someone like that for the working groups and so forth, also.
>
> DR. LEE: She is a superwoman.
>
> Any other comments about this makeup, the two ACPS members?
>
> DR. SHEK: If I may. One aspect, when you are going to make the
> decision look at the expert. I am looking at the title of the
> committee, Manufacturing. If you look at the goals, I think it is more
> CMC-type of a subcommittee. It is so purely, I believe, manufacturing.
>
> As we looked, I think, at the experts, we should make sure that part
> of the stakeholders are coming from the R&D environment. Since they
> are basically GMP regulations from Phase I clinical studies, people
> are involved purely with the regulations. But there is also the aspect
> of the future and new technology coming in.
>
> I think PAT is a good example where the push didn\'t come really from
> even R&D. It came from manufacturing, or not from the industry. In the
> future, it would be nice if we can turn it around. So, at least some
> of those eight to ten should come from an R&D environment.
>
> DR. HUSSAIN: After I put the slide, it occurred to me I missed the R&D
> group. I just had manufacturing and quality assurance, but I think,
> unless you have the R&D part of that\--I think it is important.
> Thanks.
>
> DR. KIBBE: Just a couple of things. I think that this subcommittee has
> an opportunity in front of it to basically change the way both the
> Agency and the industry work in a lot of ways and have a long-term
> impact.
>
> Changes could be advantageous for the industry in terms of efficiency,
> advantageous to the public in terms of better assurance. I am still
> struggling about making sure we have all the stakeholders and all the
> people involved and, at the same time, having all the expertise. It is
> clear that we need to have, at each one of our meetings, someone from
> the Agency that represents the field as well as someone from the
> Centers because the field is going to have to activate what is going
> on at the same time.
>
> It is clear that there are different concerns from different aspect of
> the industry but, at the same time, there are concerns from the people
> who are manufacturing testing equipment. We get a lot of good input in
> terms of PAT from them. And the international community that might be
> ahead of the curve on some things, behind the curve on others. I do
> respond quite positively to the comments that, while we were
> developing that, because we had an international flavor to it,
> harmonization came along as a consequence of fallout.
>
> So I don\'t know how you are going to be able to pack all of that into
> eight people. I am worrying about making sure that we get the right
> mix and we have the right group, and then your time lines to get some
> of things done. We also need to get a real vision for the committee
> because of its potential large impact and goals and objectives.
>
> It is going to be a daunting process the next couple of years.
>
> DR. LEE: You might be the one we would ask to chair it, Art.
>
> DR. KIBBE: I love daunting projects.
>
> DR. LEE: As we discussed, the committee is extremely important and I
> think that we need to give it some careful thought about how to
> constitute it, to make sure it is a progressive committee. I think
> something I liked hearing this morning is that someone should be
> looking out to the future. Is that the charge within this committee? I
> think so. I think this should be looked at in order to mix
> housekeeping and forward-looking activities in the same committee is
> something that you might want to consider.
>
> I am getting off the committee so I just would make a laundry list for
> my successors.
>
> Any other suggestions? What does OPS expect from this committee?
>
> DR. HUSSAIN: What we will plan to do is, in a sense, take the input
> and start working towards forming this committee and then go through
> the process that is needed to do that. Again, I think going through
> the PAT subcommittee helped because if you look, on my right, you have
> Doug and Joe always with us on the PAT so the process worked very
> well. I think we want to sort of repeat that success again.
>
> Clearly, I think that this is not just CDER now. CVM, CBER and
> everybody\--everybody has to be together on this. So it is a bigger
> challenge definitely than PAT, but I think going through that PAT
> process helped us at least create the part that will lead us to
> helping manage this more complex one.
>
> DR. LEE: Just for clarification, Ajaz, the ACPS members are by
> statute?
>
> MS. REEDY: Yes; at least two members.
>
> DR. LEE: At least two; okay.
>
> DR. MEYER: For the experts, do you have the eight to ten\--do you have
> to have geographic distribution and ethnic distribution and gender
> distribution or can you pick eight females that are experts from
> Merck?
>
> DR. LEE: What\'s wrong with that?
>
> DR. HUSSAIN: We always try to go for diversity. That is always our
> goal. Definitely, I think that is mandated for the advisory committee,
> but I think it is a bit more flexible on that. But that is always our
> goal, to go for diversity as much as possible.
>
> DR. LEE: Working groups.
>
> DR. HUSSAIN: In terms of working groups, I think what our thoughts
> were\--for example, if I take the example of cleaning validation, it
> is a very focused topic. I think there is a need for guidance there.
> If I use that as an example, then the working group on cleaning
> validation would be sort of a fact-finding and making certain
> recommendations to the committee could be formulated and asked to do
> something rather quickly and come up with something, and so forth. So
> that would be an example.
>
> But I think the numbers and the topics, I think I like what Gerry
> mentioned as part of the goal of the subcommittee is to identify these
> topics and prioritize them because there are many topics to be
> addressed. I don\'t think FDA has all the resources to start
> everything at the same time, so we have to manage that process well.
>
> So one of the charges of the first meeting of this subcommittee would
> be to simply identify those topics, prioritize and then, as part of
> the goals and objectives setting itself. So that is how we intend to
> proceed.
>
> DR. LEE: Gerry, did you want to make comments?
>
> MR. MIGLIACCIO: I would be happy to provide PhRMA\'s list of
> priorities to Ajaz to focus on. We have gone through that
> prioritization exercise. We have polled the entire PhRMA membership
> and I think there will be a lot of commonality from what you are
> thinking and what we are thinking.
>
> DR. LEE: Anything else about the process?
>
> DR. HUSSAIN: This is with the endorsement of that, and I think we can
> start taking input we have received and move forward.
>
> DR. LEE: It is still not clear to me who is appointing the members.
> The OPS?
>
> DR. HUSSAIN: We will work within FDA to bring that together. It will
> not just be OPS. It is the Office of Compliance and will involve other
> segments like Doug and other districts. So it is sort of a team
> process.
>
> DR. LEE: Thank you.
>
> Gloria?
>
> DR. ANDERSON: I would just like to suggest that, prior to asking the
> committee, after you have formed it, to formulate the goals and
> objectives. It seems to me like someone would need to take a cut a
> doing a first draft because it is not clear to me how you will know
> what your membership would look like if you haven\'t formulated
> clearly in your mind what the task is that the committee will do.
>
> DR. HUSSAIN: In many ways, I think the manufacturing\--the scope of
> the problem ranges from R&D to manufacturing to QA functions. So, in
> that sense, we think we have clearly identified what type of expertise
> and experience is needed.
>
> I think the challenge would be the stakeholders because the number of
> stakeholders are many in the sense\--I mean, we have two stakeholders
> represented here from the PhRMA and GphA but that is that is not a
> complete list of stakeholders. That will be a challenge, I think. That
> will be sort of an internal discussion and decision then.
>
> DR. LEE: Evaluation.
>
> DR. HUSSAIN: The evaluation, more I meant it\--it is sort of reporting
> back to this advisory committee, itself. PAT kept receiving good
> timely feedback in terms of that. So it is continuing that process. If
> you have any thoughts on how we could have improved the PAT process,
> itself, that would be a sort of a question on evaluation on the PAT
> subcommittee, itself, from your perspective what we could have done
> better that will help us.
>
> DR. LEE: Gloria?
>
> DR. ANDERSON: I would like to suggest on the PAT, and this has always
> concerned me, is that I don\'t think we went back to the original
> goals and objectives enough to see where we were. At the last
> committee meeting, I suggested that now that we are as far along as we
> are with the task that was set out at the beginning, that it might be
> a good time to go back and see where we are and make some
> determination about how to proceed in the future.
>
> I think that would be a good thing to do with this, particularly in
> terms of evaluation because I always look at evaluations as a means of
> determining the extent to which the goals and objectives have been or
> are being achieved.
>
> DR. KIBBE: I think this particular committee is such a broad-impact
> full committee that we probably, after we get some general guidance
> from the agency on the overall mission or vision and begin to set
> goals and objectives, we are going to have to set milestones timely as
> we look at each aspect that we are trying to look at, if we are going
> to work in one particular area to start with and move through it.
>
> I think Gloria is right. Closing the loop with advisory committees
> sometimes, as you said, \"Well, we took all that information and
> guidances are coming.\" I think the committee would like to see the
> guidance when it actually happened so that we knew that what we did
> had an outcome that was tangible and useful.
>
> Quite honestly, one of the things that I would like to see us do is
> survey our stakeholders independent of the committee for the impact of
> what is going on, maybe pre or post kinds of things, where we get a
> sense of what the industry thinks is happening today and then, two
> years from now what the industry thinks has changed and what has
> happened. That might be helpful, too.
>
> DR. MEYER: A follow up on Art\'s comment. If I have a student prepare
> an exam for me and I grade that exam, I have evaluated them. But, if I
> don\'t show them what grade they have, they don\'t know how they did.
> I think that is missing to some extent in the activities of this
> committee. So if the subcommittees prepare something for this
> committee, this committee then talks about it for two days and Ajaz
> takes it and throws it in the basket, we would never really know that.
> It just kind of disappears into the future.
>
> It might be useful for the beginning of each session of one of these
> committees, or this committee, to have kind of a review; this said to
> this and this said to us and we thought it was a crock, or we have put
> forth a guidance.
>
> DR. HUSSAIN: I think it is a very good point. In fact, it was raised
> yesterday. Dr. Lee is\--sort of this is his last meeting and he has
> been the chair for a relatively short time. Some of the things we have
> started, he will not know what happened with them unless he comes back
> to FDA to find out.
>
> DR. LEE: I don\'t want to know.
>
> DR. ANDERSON: Also, I think as new members come in, I sort of look
> back at the memo I sent to you. I have the transcripts listed, the web
> addresses. But the transcripts may not always provide the summary that
> is need to keep the continuity. I think we will try to find some means
> of doing that.
>
> DR. LEE: Very well. I think we have had some good discussion. I think
> the folks around the table probably will know exactly what to do. I
> think this is a very important subcommittee, an experiment in
> extension. I emphasize that the basis is science, risk-based, quality
> and also I will add some common sense.
>
> With that in mind, are there any questions before we take a recess? If
> not, let\'s continue at 10 o\'clock. Thank you.
>
> \[Break.\]
>
> **Manufacturing Issues**
>
> **Sterile Drug Products Produced by**
>
> **Aseptic Processing**
>
> DR. LEE: We have some presentations on manufacturing issues, sterile
> drug products produced by aseptic processing. Ajaz, are you going to
> give the introduction?
>
> **Introduction**
>
> DR. HUSSAIN: My introduction is a brief introduction. Actually, I just
> wanted to introduce Joe Famulare. He is going to take the lead to
> introduce the topic. Just two perspectives I want to share with you.
> This is probably the first manufacturing topic in this format that we
> have brought to this committee so it is sort of a new format. Also,
> what we are trying to do here is to bring all segments of the FDA
> which impact on this topic.
>
> So you are looking at Jay from CBER, Joe from CDER and Doug Ellsworth
> from the District representing those segments. The Office of
> Pharmaceutical Science, the Microbiology staff will make a
> presentation, a brief presentation, on how we are planning to support
> this initiative. So I think our goal here is to sort of listen to the
> Advisory Committee after they have a chance to listen to the issues
> being presented here.
>
> So, with that, I will introduce Joe Famulare.
>
> DR. LEE: Thank you.
>
> MR. FAMULARE: Thank you and good morning.
>
> \[Slide.\]
>
> I just wanted to address this Advisory Committee to address the topic
> of aseptic processing standards today for a number of reasons. The
> most prominent of these is the urgent need to publish guidance that
> could promote better understanding of some basic cGMP issues relating
> to aseptic processes.
>
> As we reviewed our program for the inspection of drug manufacturers
> from a risk-based perspective, we have agreed that sterile drugs are,
> in many respects, the highest risk category due to the route of
> administration and the potential for hazard to the patient. Our 1987
> guidance entitled, Sterile Drug Products Produced by Aseptic
> Processing, noticed that the Agency would issue revisions in the
> document from time to time when it recognized the need.
>
> Through the regulatory efforts and comments submitted by interested
> persons, with this knowledge, the following evolution and technology
> stand as an understanding of aseptic processes, we embarked on the
> task of updating this 1987 guidance in 1997. The intention of the
> revision was to improve clarity and explanation of cGMP issues to
> better facilitate industry compliance.
>
> \[Slide.\]
>
> This effort, as Ajaz mentioned, is a joint CDER, CBER and ORA work
> product. We have here, of course, Doug Ellsworth representing the
> Field Drug Committee in ORA, the field, and Jay Elterman from CBER,
> the Director of the Division of Manufacturing of Product Quality in
> that unit.
>
> The overarching goal of FDA in issuing revised guidance is to provide
> a document that will facilitate improved industry compliance. We
> receive questions on practical and technical issues that have formed a
> clear pattern and plan to overlap very much with issues that are very
> often cited in regulatory citations, whether they be 483s or warning
> letters.
>
> We want to bring clarity to these quality issues that are sometimes
> murky by providing sound understandable principles and without being
> overly prescriptive. We are providing this unprecedented opportunity
> for a preview of our current thinking because we believe it is urgent
> for guidance on aseptic processing to issue.
>
> Thus, we have this concept paper here today to solicit feedback and we
> are trying to take in all the comments from this advisory committee in
> order to publish the draft guidance as the next step.
>
> \[Slide.\]
>
> Just to cover the concept paper, one of the basic things that we did
> was to improve the format over the 1987 Guidance. Hopefully, it is
> more user-friendly with a table of contents and headings and easy to
> read and follow. We have added definitions of air-lock components,
> colony-forming units, dynamic conditions, endotoxin, gowning
> qualifications, barrier and isolator technologies, et cetera, so that
> we wanted to bring things in line with today\'s current technologies.
>
> We have also updated old sections. One of the areas, of course, would
> be the evolution of the sterility testing in the USP. And we have
> added some new sections, again based on advances of technology and
> dealing with issues that we see as needing the most guidance such as
> personnel, the use of isolators and early processing steps are
> particularly a concern to the biologic industry.
>
> \[Slide.\]
>
> This guidance has been requested by the industry. Again, we hope to
> promote better understanding of GMPs. Industry organizations such as
> PhRMA and PDA have requested updating guidance on an expedited basis
> to address areas where there is confusion on what the minimal GMP
> standards are. FDA, of course, agrees that we wanted to provide this
> guidance.
>
> By having proactive communication of our expectations, we hope for
> firms that are building or modifying facilities to do that in an
> efficient, money-saving way, and to, again, clarify issues where
> questions persist.
>
> \[Slide.\]
>
> In answering the question why to improve the guidance, it is important
> to reflect the evolution of knowledge, remove that information that is
> obsolete from our 1987 Guide that is out there, and fill major voids
> that have been illuminated over time. We want to reflect current
> standards and, importantly, we want to incorporate the latest
> scientific principles.
>
> \[Slide.\]
>
> We want to reflect uniformity between the Discussions and Biologics
> Center and, of course, have the field represented well in terms of the
> implementation by field investigators in looking at aseptic process
> manufacturing. We want to move forward on those issues that have been
> debated year after year in working together on new matters of
> importance so that the most important issues are covered during our
> inspections and are given emphasis by companies.
>
> \[Slide.\]
>
> Going back in a little bit of history, the original 1987 Guidance was
> written in lieu of regulations and the process began, really, around
> 1980. In the Preamble of the GMP regulations of 1978, it said that,
> while the GMP regulations address finished dosage-form drugs, that
> many unique and critical variables attendant to sterile drug
> manufacturing would be best addressed thought the publication of
> additional regulations on both SVPs and LVP; that is small-volume
> parenterals and large-volume parenterals.
>
> Most of you know that FDA ultimately wrote regulations for LVPs but
> they were never finalized. In lieu of the regulations, of course we
> provided the Aseptic Processing Guidance of 1987. The choice of the
> guidance route, we hope provided industry with a better understanding
> of FDA\'s interpretations of the regulations while still leaving
> significant flexibility for manufacturers by virtue of not
> establishing mandatory standards.
>
> That 1987 guidance, we believe, proved effective in answering some
> recurrent questions at the time but, over the last several years, we
> have recognized the gap of updated cGMP guidance in high-risk areas of
> sterile drugs. Industry representatives have repeatedly asked for the
> issuance of this document since our inception of announcing that we
> were working on this.
>
> \[Slide.\]
>
> It is important to address the quality of sterile drugs as a priority
> for the Agency. One of the reasons that, of course, this ends up as
> being one of the first things that we look at, as we look at the
> formulation of this new manufacturing subcommittee. We see that there
> are persistent problems that need to be resolved and averted in the
> first place.
>
> It is very important to maintain a steady supply of many of these
> drugs to the American public. We see that they represent very
> important therapies. Very often parenteral manufactured products end
> up being areas where we have shortages and there has certainly been
> publicity in the recent year or so, whether it be certain biologic
> products such as flu vaccine and other types of vaccine products that
> not only are important therapies but are also national security
> concerns.
>
> So it is important to have this area covered in a way to avert these
> problems in the first place. Of course, handling these in the
> regulatory mode is a time-consuming problem for both FDA and the
> industry.
>
> So we are hoping to have better adherence to cGMPs for sterile
> products through improved guidance, improved inspectional focus and
> better understanding of the scientific principles.
>
> \[Slide.\]
>
> We could see, in looking at the recalls from Fiscal Years \'99 through
> 2002, that certainly lack of sterility assurance has represented a
> large number of recalls that have occurred over these last couple of
> fiscal years so, again, reinforcing the need to avert these problems
> and to find out what the problems are in advance and to work through
> this guidance in identifying those areas where we could give the best
> guidance to avert these types of problems.
>
> Many of these result as an outcome of cGMP inspections. You can see,
> just looking at Fiscal Year 2002, we ended with some 52 recalls in
> this particular area.
>
> DR. MOYE: Could I ask just a clarification while that slide is up?
> What do the colors mean?
>
> MR. FAMULARE: They just distinguish the different years.
>
> DR. MOYE: They were all blue except for the last two.
>
> MR. FAMULARE: There is no other meaning other than to distinguish the
> two years. I apologize for not having a consistent pattern of thought
> for the colors.
>
> DR. MOYE: That\'s all right. I just didn\'t want to miss anything.
>
> DR. KIBBE: Is there an explanation for the dramatic change between
> \'98 and \'99?
>
> MR. FAMULARE: Many of these result as a result of cGMP inspections
> that have occurred. In one particular instance, and this is top of my
> head, I think one company that was under a regulatory concept decree
> actually cleaned up the marketplace of their products rather than to
> try and evaluate all the different sterility problems that may have
> occurred from products that they were, overall, eliminating from the
> marketplace.
>
> So, as a matter of expediting removal of suspect products, the company
> removed them all and each product represents a separate recall
> incident. So it is not companies, per se, but individual products.
>
> Any other questions on this slide?
>
> \[Slide.\]
>
> Important to consider for aseptic processing is that there are many
> variables that occur in aseptic processing. So, in preparing this
> guidance, we had in mind that aseptic processing requires daily
> vigilance and attention to many details which is certainly a true test
> of cGMP conformance.
>
> Adherence to procedures and details is important and fundamental to
> sterility assurance. Process consistency in aseptic processing is of
> utmost importance. An overriding objective, of course, is that each
> unit produced in a batch be free of microorganisms.
>
> In looking at sterile drugs, in terms of our risk-based approach, as
> Ajaz mentioned in looking at the goals of the cGMPs for the 21st
> Century, as a product class, of course, sterile drugs can represent
> hazards to a patient and an unacceptable risk to patients that may be
> posed by contaminated drugs.
>
> \[Slide.\]
>
> Failure to adhere to cGMPs in the instance of aseptic processing can
> have an impact on product safety and efficacy and, therefore, this
> whole category of drugs is a top priority for inspectional coverage is
> a risk-based inspection approach.
>
> \[Slide.\]
>
> In looking at the risk-based approach, we need to analyze what are the
> causes of contamination and where are the potential roots of
> contaminations in a firm\'s process. We need to focus in our guidance
> on the issues of most concern, those critical control points. So these
> are the areas that we will be looking for comment as individuals have
> looked at the concept paper that we have put out there to see that we
> have put proper emphasis on these issues of most concern.
>
> \[Slide.\]
>
> Good science, of course, again, a recurring theme of today in
> focussing on these issues. We want to have a scientific-based approach
> to cGMP emphasized in the concept paper. In putting together this
> paper, there were certain key sources that were looked at; scientific
> journals, technical documents, various textbooks, vector illuminated
> by facility-contamination findings when we actually had the
> opportunity, as FDA investigators or even as people in the Office of
> Compliance that review the results of these investigation reports,
> have actually had hands-on experience in seeing what the results of
> those investigations are and what the findings of contamination have
> been.
>
> Very importantly, we hope to have captured within this document the
> results of our cGMP case reviews and the many cases that we have
> looked at, both particularly CDER and CBER, at our level, to see what
> the commonalities were, to see what those areas of emphasis need to be
> which led to our regulatory entanglement so that we could take that
> experience and bring it forth into this concept paper and eventually
> into guidance to address those issues.
>
> \[Slide.\]
>
> I will just briefly\--Ajaz went over this in great detail this
> morning\--the cGMP for the 21st Century to make sure that, as we look
> at this concept paper that will eventually be our guidance, that we
> outline the risk-based approaches that will better focus FDA\'s and
> industry\'s resources, we make, as is noted in this concept paper, a
> good system better, focus on critical process parameters, critical
> control points and yet be flexible enough to encourage innovation in
> the industry.
>
> So, while these are the major goals of the cGMP for the 21st Century
> Program that was announced this past August by the agency, we want
> folks to keep this in mind in looking at the concept paper, that we
> keep sight of theses goals as we put forward our ideas in this concept
> paper.
>
> \[Slide.\]
>
> We have to recognize the diverse nature of the industry and that new
> guidance will address this essential practicality while also providing
> meaningful insight into what FDA\'s expectations are. We need to
> encourage innovation by acknowledging new technologies and by
> liberalizing some old standards where it is appropriate.
>
> For example, in one of the examples that I could think of in the
> concept paper where we had a specific number for the rate of air flow,
> now this could very often be demonstrated by smoke studies. It is
> important to remember, again, and I know we say this every time FDA
> issues a guidance but I will emphasize it again, that this will be a
> guidance and not a regulation so there is latitude for flexibility.
>
> \[Slide.\]
>
> So, to focus on today\'s broad question in looking at this concept
> paper. What additional considerations are needed to ensure that the
> proposed guidance contributes to the improvement of the aseptic
> manufacturing process across the industry, improves consistency in the
> FDA inspection process, and, at the same time, can encourage
> innovation in the aseptic-process manufacturing arena.
>
> \[Slide.\]
>
> Continuing our broad questions, is FDA\'s current thinking on these
> topics as outlined in the concept paper well grounded in science and
> sufficiently detailed to provide industry with clarity on FDA\'s
> expectations with respect to assuring appropriate quality of sterile
> drugs by aseptic processing?
>
> \[Slide.\]
>
> We see, again, a compelling need for this revision to the 1987
> guidance. The concept paper represents our current thinking to date
> and we really value your feedback, particularly on the level of
> specificity. There is always debate as to whether we have targeted
> what we are looking for too specifically and, at the same time,
> allowed latitude for individual innovation or individual firms\'
> needs.
>
> We will listen carefully and do a comprehensive review of all the
> advisory comments and, of course, then we will take this advice and be
> able to put this best effort as the results of the comments we get
> from the advisory-committee setting here today into publishing a draft
> for public comment.
>
> I just want to end by thanking all the internal constituents within
> FDA that have worked very diligently. As you see, the project started
> in 1997 in order to gain a consensus within FDA to put out this
> concept paper. Those are the various groups with CDER, OPS and OC, ORA
> and CBER.
>
> Thank you.
>
> DR. LEE: Thank, you, Joe.
>
> Any immediate questions?
>
> DR. HUSSAIN: Joe, if you want, or I think we need to introduce the
> invited guests to this section.
>
> MR. FAMULARE: Okay. We will have, as speakers, and I don\'t have the
> names in front of me except right over here, various representatives
> of the FDA to introduce various topics or subjects throughout the day.
> But we also have some invited guests such as from the PDA, Russ Madsen
> who will be talking this morning, giving the PDA perspective.
>
> We have Berit Reinmuller who will be giving a technology presentation
> on air flow and air velocity. And then we will have various FDA
> individuals really serve to structure the topics of the day. Actually,
> the next presenter will be Rick Friedman who will set the stage for
> the various issues, the five main issues, that will be covered out of
> the guidance.
>
> Not to steal his thunder, I will let him introduce those topics, but
> he will be the first speaker broadly introducing those topics. He will
> be back again this afternoon to introduce one of the five topics along
> with Kris Evans from ORA, Bob Sausville from CBER and Brenda Uratani
> from CDER Compliance. Again, representing the collaboration on this
> document, we will have from OPS, from the review side, also giving a
> brief presentation on the interrelationship of the review and the GMP
> side, David Hussong.
>
> Did I forget any names, Ajaz?
>
> DR. HUSSAIN: Also, I think if you could just go around the table and
> introduce the new invited guests, also.
>
> MR. FAMULARE: Okay.
>
> DR. LEE: Or we could have them identify themselves.
>
> MR. FAMULARE: Oh; the other guests? I don\'t have the list in front of
> me. Those guests. That would be easier just because I don\'t have the
> names in front of me. I\'m sorry.
>
> MR. MUNSON: Terry Munson. I am a consultant from KMI/Parexel. Was
> ex-FDA, worked in the Office of Compliance at CDER.
>
> MS. LOWERY: Sandi Lowery, a consultant from Quality Systems
> Consulting.
>
> DR. BURSTYN: I am Don Burstyn from Alkermes Pharmaceutical Developer
> and Manufacturer.
>
> MS. DIXON: I am Ann Marie Dixon from Clean Room Management Associates.
> I am a consultant.
>
> DR. KORCZYNSKI: Michael Korczynski, Principal, Mikkor Enterprises.
>
> DR. LEE: And Professor Reinmuller from Stockholm?
>
> DR. REINMULLER: Berit Reinmuller from the Royal Institute of
> Technology in Stockholm, Sweden.
>
> MR. MADSEN: Russ Madsen from PDA.
>
> DR. LJUNGQVIST: Bengt Ljungqvist, from the same university as Berit
> Reinmuller.
>
> DR. LEE: I think that covers just about everybody before lunch. Thank
> you.
>
> MR. FAMULARE: Rick Friedman will be the next presenter. One of the
> other guests is Jeanne Moldenhauer.
>
> DR. LEE: It is hard for me to keep track of all these names.
>
> Rick, you have twenty-five minutes.
>
> **Contamination**
>
> MR. FRIEDMAN: Thank you and good morning. My name is Rick Friedman. I
> work for the Center for Drugs, Office of Compliance.
>
> \[Slide.\]
>
> Aseptic processing is an intricate and complex method of producing
> sterile medicines. Since the publication of the 1987 Guidance
> Document, there has been an evolution in the knowledge and
> understanding of aseptic processing. Data-analysis experiences shared
> through pharmaceutical-industry publications and conferences have
> contributed significantly to this enhanced understanding.
>
> CDER, CBER and ORA have issued a joint concept paper for your
> consideration that comprehensively outlines the cGMP areas that we
> believe are in most need of guidance. The cGMP specifically addressed
> the need to monitor and control sources of variability in the
> manufacturing process. GMP representatives throughout FDA regularly
> speak of identifying the critical control points for a given process
> and the need to support the process with well-conceived design control
> and maintenance procedures.
>
> Using this mind-set of sources of variability and critical control
> points, our concept paper stresses major indicators of quality for an
> aseptically processed parenteral drug.
>
> These key determinants of sterile drug quality also make up the main
> theme of this presentation which will provide a bit of the theory and
> practice that have formed the foundation of our current thinking.
>
> After discussing some of the science base, I will address the practice
> through sharing a few case studies that illustrate where one or more
> critical control points failed with the consequence of nonsterility.
>
> \[Slide.\]
>
> It is very difficult to quantify risk but there are a number of useful
> tools in the literature describing metrics often used by the
> pharmaceutical industry. One method is discussed by Paul Noble in the
> July or August 2001 PDA Journal. He uses the popular failure mode and
> effects analysis, FMEA, method to indicate which parts of a firm\'s
> operations present most GMP and public-health risk and, therefore,
> deserve the greatest attention.
>
> In discussing the three aspects of this method, he starts with the
> first component, reducing the severity of risk by process changes or
> product redesign. He states an example of reducing risk severity would
> be exploring development of a terminal sterilization process for a
> product that is aseptically produced.
>
> The second component of this method is reducing the probability of
> occurrence of risk. Noble states that these improvements can have
> \"long-lasting benefits\" including efficiency gains and avoiding
> future problems. He names the following systemic improvements;
> \"process automation, tighter controls upstream in the process and
> implementing new technologies such as isolators to reduce the chance
> of microbiological contamination.\"
>
> He then discusses the third category, the detection of failures. He
> characterizes validation tests as \"intensified monitoring\"\--that is
> a great definition of validation\--\"which should detect flaws or
> weaknesses which may not be normally observable. A media fill is a
> good example of a validation test.\"
>
> He notes that, \"Conducting a medial fill will not, by itself, reduce
> the chance of contamination. Only a proper corrective action response
> to the detected flaw or weakness will do so.\" We found it notable
> that these examples named by the author as beneficial in preventing
> the costs associated with product-quality problems also happen to
> mirror the many principles included in our concept paper and these
> issues will be among our major topics of discussion today.
>
> \[Slide.\]
>
> Our revision of the aseptic-processing document began by asking this
> basic cGMP risk question; what are the potential sources of
> contamination in an aseptic process? In an effort to answer this
> question, the concept paper focuses on selected aspects of the aseptic
> process and facility that, if not maintained in a good state of
> control, can lead to the contamination of finished units of a
> parenteral drug.
>
> We also asked the question, what measurements are most valuable in
> indicating sterility assurance. While cognizant that some factors of
> the manufacture of a drug are more influential than others, they get
> different weights, we acknowledge what so many before us have also
> acknowledged, that, if an aseptic-process operation does remain in
> control throughout processing, contamination may occur that is
> unlikely to be detected in the end-product sterility test of a very
> small number of units.
>
> Instead, there are number of personnel, environmental and mechanical
> variables that must be considered to make a reliable assessment of
> whether the aseptic operation is under control.
>
> We also concluded that such metrics should be founded in
> scientifically sound in sufficiently representative sampling plans so
> that meaningful data can be used to evaluate whether a batch was
> produced under adequate conditions. We felt that we should focus on
> those metrics that can provide a signal of an emerging or existing
> route of contamination.
>
> In short, our compound addresses areas of GMP that, if not controlled,
> can impact on drug safety and efficacy and we will not need to go into
> explanation for the group assembled today regarding the fact that
> parenterals contaminated due to poor manufacturing conditions have, in
> fact, led to infections.
>
> \[Slide.\]
>
> This slide is an attempt to visually illustrate the complexities of
> aseptic processing. One might call it a macro-model of daily
> \"sterility assurance,\" and sterility assurance is in quotes because
> we know the difference, obviously, between SAL, sterility assurance
> level, which is predictable in internal sterilization and the vagaries
> of aseptic processing.
>
> This macro-model of daily \"sterility assurance\" includes the
> big-ticket facility and process-control factors that form the basis of
> overall process control. The first influential cGMP element is
> personnel\--I will go around clockwise and maybe give an example or
> two quickly\--but, personnel, facility and room. The D and M mean
> design and maintenance. The kind of question we would ask from a GMP
> perspective is is the facility constructed to accommodate the constant
> dynamic interaction between rooms and does the design create
> contamination routes. Is an adequate maintenance program in place to
> address the gradual breakdowns in facility infrastructure.
>
> Aseptic processing line design and maintenance process\--this refers
> to both the filling process and the unit-sterilization operations that
> support it, autoclaving, et cetera, dry-heat depyrogenation. Does
> personnel and material flow through the facility increase the chance
> for tracking contaminants into the aseptic-processing room? Do the
> ergonomics of process flow or equipment configuration create difficult
> aseptic manipulations, unnecessary activities too close to the aseptic
> zone or other issues which undermine confidence in the sterility of
> each unit?
>
> HVAC and utilities; response to deviations and environmental control
> trends; disinfection regimen and actual practices, media fills; and,
> of course, the essential role played by the quality assurance and
> quality-control units.
>
> \[Slide.\]
>
> So there are a number of potential sources of contamination that must
> be addressed in accord of cGMP. The existence of these many
> interdependent sources of variability are succinctly summed up in this
> excerpt from ISPE\'s Sterile Facility Guide which emphasizes that the
> aseptic-processing room does not exist in a vacuum. The room is part
> of a dynamic integrated system that is affected by the activities that
> take place both within it and around it. As such, they write that a
> firm must employ, \"a strict design regime not only in the process
> area but the interactions with surrounding areas and movement of
> people, materials and equipment so as not to compromise aseptic
> conditions.\"
>
> In other words, the microcontamination can eventually migrate to the
> critical zone and cause product nonsterility if attention is not paid
> to the holistic design, control and maintenance of the facility.
>
> \[Slide.\]
>
> There will be a lot of discussion today about environmental-control
> design and, of course, personnel. So let\'s look closer at some quotes
> from journals and textbooks of the topics of personnel design and
> environmental control. Even with a good facility and processing line
> design, poor personnel practices can upset the delicate balance of the
> aseptic operation. With regard to aseptic interventions, our \'87
> Aseptic Guidance points out that any manipulation of the sterile
> dosage-form containers and closures involves the risk of contamination
> and, thus, must be carefully controlled.
>
> The late Professor Kenneth Avis of the University of Tennessee spoke
> about the need for \"continued vigilance throughout the entire
> manufacturing process\" back in 1971 in the PDA Journal. The
> researchers Ljungqvist and Reinmuller state, in their textbook,
> Minimizing Contamination Through Proper Design, that, \"Unstable
> situations are, in most cases, caused by the influence of arms and
> hands.\"
>
> We are pleased that Ljungqvist and Reinmuller, whose research has been
> widely cited by industry and regulatory authorities alike could travel
> here from Sweden to discuss their research today. They have made a
> significant contribution to parenteral science in their studies of the
> influence of design, personnel practices and environmental control on
> product contamination.
>
> \[Slide.\]
>
> Here are a couple of references on environmental control. Let\'s look
> at the second one. Sinclair and Tallantire performed studies to
> determine if a correlation between Class 100 control and contamination
> prevention exists. Using a blow-field-seal line, BFS line, and a known
> microbiological challenge level, this research team established that
> there was a \"definable direct relationship between the fraction of
> product contaminated in the lot and the level of microorganisms in the
> air surrounding the machine.\"
>
> This type of basic research study is useful in that it showed a
> correlation between an increasing number of microcontaminated units
> and the degree of contamination in the immediately adjacent machine
> containment room.
>
> \[Slide.\]
>
> Among the recommendations was that local protection of the operation
> could be improved to make contamination risk to the filling step more
> independent from the adjacent operation, the adjacent environment.
> Sinclair and Tallantire also found that product protection at lower
> velocities was inadequate to prevent contamination. As velocity
> increased in this system, the number of nonsterile units decreased.
>
> They conclude, for the systems studied, \"a reduction in contamination
> of blow-field-seal product is achieved by a \'high-quality and
> high-volume air shower to protect the filling zone.\'\"
>
> I have just reviewed just some of the numerous useful references that
> are relevant to our discussion today. Based on these and many other
> references, there is concrete foundation in the Year 2002 for the
> statement that, \"Design, environmental control and personnel
> practices are each crucial to an aseptic processing operation.\"
>
> You might ask, at this point, how does this statement of theory
> correspond to our actual experiences with industrial-contamination
> problems? The answer to this question is that we see a cross-section
> of sterility failures each year that illuminate commonalities in the
> source of contamination. Lack of adherence to cGMP in one or a
> combination of these three areas has been central to the vast number
> of these.
>
> This brings us to some case studies that illustrate the origins of
> some of these contamination problems. Some have asked the question,
> what makes three validation batches so special. Why not one, or five
> or ten? A three-lot study may, indeed, not be perfect but it does
> generally provide a reasonable degree of reproducibility given
> practical and business limitations.
>
> A commercial process is tested with three different lots, each with
> their own unique variables presented by a given day in it is somewhat
> unpredictable events and, if done well, at the conclusion of the
> three-batch study, a more enlightened understanding of the state of
> commercial process control will be gained.
>
> \[Slide.\]
>
> This case study is a good illustration of the value of showing
> reproducibility. In this case, a firm had a pristine clean facility
> for two or three years, no media-fill failures. It is a large
> manufacturer. And then, one day, it had a media-fill failure where
> approximately 60 percent of the vials were contaminated.
>
> The failure was considered to be a spurious event. Nonetheless, there
> were some corrections that were made to the firm\'s satisfaction to
> improve different areas which were thought to, in fact, correct the
> issue.
>
> The firm looked at the FDA guideline and PDA\'s Technical Report No.
> 22\--both note that three lots are needed if a line falls out of
> qualification\--for revalidation. So they ran the first media-fill
> batch and found no contamination.
>
> They ran a second media-fill batch and this one was over 95 percent
> contaminated over 5,000 vials. The third media-fill batch was run. No
> contamination. So, one can see, if one batch was run, a firm would
> return to production and release of commercial lots without knowledge
> that a nonsterility problem still existed.
>
> The root cause in this case had to do with personnel. Isolates in both
> failures, both of the media-fill failures, were common skin-borne
> microbes. They found that the gowning level was inadequate. Part of
> gown was nonsterile and the sleeves were sterile and maybe other parts
> of the gown were also sterile. But part of the gown was nonsterile and
> they felt that the aseptic technique was questionable and there was
> also some skin exposed.
>
> Now, work was being done under a hood so presumably, by doing the work
> under the hood with sterile sleeves and sterile gloves, there
> wouldn\'t be contamination. But, obviously, this underscores the
> importance of full gowning and the fact that touch contamination and
> cross contamination from nonsterile and sterile parts of the gown is a
> practical reality.
>
> The corrections to resolve these issues in this case were enhanced
> personnel and environmental monitoring performed in the near term. But
> the firm did, and one of the things that we are stressing in this
> guidance, increase in automation, removing personnel as much as
> possible from the aseptic processing by later modifying the line to
> allow for sterilization in place. They no longer have an aseptic
> connection. So they have taken that risk out of the process.
>
> \[Slide.\]
>
> This recent case study occurred at a major manufacturer, also. During
> the inspection of this facility, the inspection team actually entered
> the clean room on a nonproduction day and found mold in the
> aseptic-processing room. Mold had built up in between two walls in
> which the return vent was located.
>
> The investigators observed a significant area covered with greenish
> hard, dry mold drippings that extended out of the vents. It was
> evident to them that this visible mold buildup in the air returns
> should have been readily noticed and it appeared that it had been
> there for quite a while.
>
> The firm had validated a number of sterility failures without an
> adequate basis, a laboratory causality. In addition to the highly
> unusual event of our investigators seeing the mold in the room during
> the inspection, the firm had detected a clear adverse trend showing
> persistent mold contamination in the area during environmental
> monitoring. The firm had a trend of several sterility failures and the
> inspection team found that the same molds found in the environment
> were also named as isolates in the sterility test positives.
>
> \[Slide.\]
>
> Here is an abbreviated summary of some more cases where adequate
> procedures were not followed to prevent microcontamination. The
> origins of contamination listed on the next two slides are those named
> in the firm\'s actual written or media-fill and sterility-failure
> investigations.
>
> Just to go through these quickly. Aseptic practices is named very
> frequently in media fill and sterility failures. Personnel returned
> after a long winter shutdown. We have seen this scenario repeated a
> few times over the years. There might not be the currency of knowledge
> coming right back from a one or two-week vacation and the recall of
> the importance of vigilance in aseptic technique. In this case, that
> was the attributable cause.
>
> \[Slide.\]
>
> In another case, an operator reached over open vials to remove a
> fallen vial on the line with gloved hands. This was observed and it
> was a common practice. This was considered to be the cause of the
> failure. Poor personnel flow has also been named in media-fill and
> sterility-failure investigations.
>
> Poor aseptic connections; I just gave an example but we have seen that
> many times just this year. Poor sanitization procedures deficient or
> poorly executed; I have never seen more cases of that than in the last
> year. Construction in another room of the same floor of a facility
> caused increased airborne contamination. This has happened a number of
> times. It is well-established in bioaerosol and other textbooks
> including the Macular Textbook of Aerosols showing that when there are
> construction facilities, mold can be widely dispersed in the facility
> and make it to places you would never expect it to make it.
>
> In this case, a Bacillus was the contaminating organism. There is a
> specific species that made it all the way down the lengthy hallway
> through the aseptic-processing facility airlock\--that hallway was
> uncontrolled because it is part of the office environment, et
> cetera\--through the aseptic-processing facility air lock\--now, you
> are in aseptic facility\--into other clean rooms, into the
> aseptic-processing room, finally to the aseptic-processing line to the
> critical zone and into the product, all the way across the facility
> where construction was taking place.
>
> There have been a number of sterility failures in a several-week
> period with this isolate in the product that coincided with the
> construction. The environmental monitoring showed an atypical trend of
> this organism and the firm concluded migration of spores from the area
> under construction was, in fact, the root cause of the sterility
> failures.
>
> \[Slide.\]
>
> Another case, a new line was put together, installed. An HVAC was
> installed. The line was signed off as qualified, the HVAC systems,
> signed off as qualified by everybody involved with the validation and
> qualification report. But, to prove out that this process actually was
> in control, they did what firms do when they have major changes, as
> again recommended by PDA and FDA, they did a media fill. The media
> fill demonstrated inadequate HEPA seal and, over 90 percent of the
> vials in the batch were contaminated.
>
> Velocity through HEPA filters. It has happened a couple of times in
> the last few years. I will tell you one quick story. In the case
> detailed on this slide, the firm had replaced a fan and installed the
> wires with reverse polarity so the fan ran backward and counteracted
> the other fans in the HVAC unit.
>
> This problem was not detected by facility monitoring systems including
> a probe that was monitoring pressure drop across the filters and there
> was no check of velocity at the time to confirm that the installation
> went well because a like-for-like change was not considered to be
> significant in the change-control procedures.
>
> The firm ran for three months under these conditions. When they ran a
> media fill, they found eleven contaminated units in about 18,000
> vials. They attributed the failure to velocity problem.
>
> Finally, there are a number of cases where we have seen mechanical
> failures of filling tanks, main-pump failure, cooling system, leaks at
> joints or pin holes. All of these have been named in field alerts and
> in media-fill and sterility-failure investigations.
>
> \[Slide.\]
>
> With this background, we have worked to update our Aseptic Processing
> Guidance to address persistent areas of cGMP deficiency. Clarifying
> basic cGMP expectations will be beneficial to all of us in promoting
> uniform interpretation of a number of big-ticket issues that are
> unnecessarily murky. This advisory committee meeting provides FDA with
> an excellent opportunity to receive feedback on our aseptic-processing
> concept paper on these five important topics; sterilization options,
> aseptic-processing-design evaluation and contamination prevention,
> media fills, environmental monitoring and personnel issues.
>
> \[Slide.\]
>
> I will close, in the last couple of slides, with just some specifics
> on the contemporary cGMP philosophies behind our concept paper. One of
> the main objectives was to recognize the advantages of new technology,
> automation and facility improvements. For instance, the compound
> acknowledges benefits of isolator technology by stating that isolators
> appear to offer and advantage over classical aseptic processing
> including fewer opportunities for microbial contamination during
> processing.
>
> So we are noting the tangible improvement afforded by isolator systems
> as well as acknowledging the lower gowning requirements, lower
> clean-room classifications and the ability to campaign, which is a
> departure from the old twenty-four-hour turnaround manufacturing
> paradigm.
>
> We also emphasize the need for a well-conceived design. For example,
> we discuss the use of air locks to provide better
> aseptic-processing-facility control. While stating that air locks are
> useful in multiple places, the only place where we advise that an
> airlock should be installed is at the entrance to the
> aseptic-processing facility that directly interfaces with the
> unclassified plan area.
>
> We use this example as we believe it presented the clearest risk to
> assuring predictability of clean-room air quality. We liberalized some
> old standards including velocity. We state that velocity parameters
> established for each processing line should be justified and
> appropriate to maintain laminarity and air quality within the defined
> space.
>
> We have relegated the old 90-feet-per-minute number to a footnote and
> acknowledged that it is often used. The design section of the concept
> paper stresses modern principles of reducing direct personnel
> involvement in aseptic operation through use of barriers and increased
> automation, moving personnel further and further away from the
> product.
>
> As an example, the BFS Section notes that blow-field-seal operations
> are highly automated and require reduced human intervention. In order
> to increase latitude for new technologies, we have loosened up the
> language in other places, also. This acknowledges that there may be a
> prevailing standard that should be, at the minimum, used for many of
> the applications, but there are also alternatives that are prominent.
>
> One of the ways that we are assuring latitude is through liberal use
> of qualifying phrases such as \"where appropriate,\" \"where
> necessary,\" in some cases, \"as necessary,\" \"generally,\"
> \"normally.\" As a means of comparing the \'87 guidance to the concept
> paper, we did a search and found thirteen uses of such latitude
> phrases in the \'87 guidance. We are now using fifty-three such
> qualifying phrases in the concept paper for latitude.
>
> \[Slide.\]
>
> We have been listening to comments from industry throughout our
> revision of the Aseptic Processing Guidance and it has impacted on the
> content of the concept paper you have before you today.
>
> I hope I have provided a useful briefing this morning on some of the
> scientific and practical underpinnings behind our current thinking and
> risk-based philosophies that we believe are instrumental in preparing
> a revised guidance that will be most useful to the industry and FDA.
>
> At the end of the day, agreement on targeted cGMP systems to detect
> trends before product contamination occurs will achieve the goal that
> is shared by all of us, a higher confidence in sterile drug quality.
>
> Thanks for your attention and we look forward to your comments.
>
> DR. LEE: Thank you very much. Would you like to take one or two
> questions?
>
> Any questions for Rick? If not, thank you.
>
> Next on the agency is David Hussong. David spoke to this committee
> before and he is going to remind us about microbiology.
>
> **Microbiology Review Perspective**
>
> DR. HUSSONG: Good morning. Thank you for the opportunity to describe
> the review role in the regulation of sterile products.
>
> \[Slide.\]
>
> The regulatory oversight of drug manufacturing and marketing is done
> by multiple organizations at FDA each looking at different aspects of
> the product and process. Regulatory review of drug application is done
> by specialized review scientists at the Centers. Review groups in the
> Center for Drug Evaluation are aligned according to scientific
> discipline.
>
> Since sterile drug products are unique by their microbiological
> quality attribute of sterility, applications for sterile products are
> sent to the microbiologists for specialized review.
>
> \[Slide.\]
>
> During drug development in the investigational new drug, or IND,
> phase, products are reviewed to establish safety goals and minimize
> patient risk. Manufacturing process development is then monitored
> during the IND and data are generated on processing experiences.
>
> By the time drug applications are submitted, manufacturing process
> experience has been gained. The product specification tests and
> acceptance criteria and process requirements are available, then, for
> regulatory review. The reviewer evaluates whether the manufacturer\'s
> process and controls are appropriate and whether the process controls
> answer the appropriate questions to assure process control.
>
> The entire manufacturing process, its controls, the manufacturing
> facility need to be appropriate for each specific product to be
> marketed.
>
> \[Slide.\]
>
> New drugs and generic drugs undergo product-quality microbiology
> review at the Center for Drugs. The microbiological reviewers evaluate
> the sterilization processes and their validation, test methods and
> acceptance criteria. According to the specific conditions of each
> product and process. \[The text of part of this slide was not
> recorded.\] Sterility is an absolute concept and it cannot be
> determined by any test.
>
> Since there can be no absolute determination of sterility, then some
> risks must be accepted. Scientific evaluation can assess those risks
> related to each product and process.
>
> \[Slide.\]
>
> The guidance the reviewers used is provided in a 1994 document that
> was reprinted and is posted on the web. It defines what is to be
> submitted in application for drug products that will be marketed as
> sterile. The introduction to the 1994 Guidance states, \"The efficacy
> of a given sterilization process for a specific drug product is
> evaluated on the basis of a series of protocols and scientific
> experiences designed to demonstrate that the sterilization process and
> associated control procedures can reproducibly deliver a sterile
> product.\"
>
> Data derived from experiments and controlled procedures allow certain
> conclusions to be drawn about the probability of nonsterile product
> units sterility assurance level. Based on the scientific validity of
> the protocol and the methods as well as the scientific validity of the
> results and conclusions, the Agency concludes that efficacy of the
> sterilization process is validated.
>
> The 1994 Guidance details the elements of validation experiments,
> allows latitude for new experimental methods and criteria and provides
> for approval of these following critical review by experienced and
> qualified scientists. That document does not, however, provide
> specific cutoff points, limits and levels. Those are usually
> determined by the firm based on their experience and the product they
> are making.
>
> \[Slide.\]
>
> In the Center for Drugs, currently thirteen microbiologists perform
> these reviews. Eleven hold doctorate degrees with dissertations in
> microbiology. Among the microbiologists doing the new drug reviews,
> there is over 120 years experience in FDA and/or sterile product
> manufacturing.
>
> These reviewers include experts in heat processes, filtration, test
> methods development, microbial kinetics, environmental microbiology
> and clinical microbiology. Each has experience in aseptic-processing
> method and the staff had experience in guidance development.
>
> The microbiologists in the Office of Pharmaceutical Science have
> offered commentary to this document and look forward to developing a
> rationale and cohesive document that will allow FDA to speak with one
> voice and with meaning.
>
> It is not certain what forum this concept paper will take, whether it
> would be better to have it address FDA\'s training or the regulated
> industry. In a recent publication, the most recent from the Journal of
> Pharmaceutical Science, two prominent authors describe problems which
> have occurred recently where investigators have demanded tests or, in
> the words of these authors, unnecessary and they also describe them as
> dangerous.
>
> We all know that there is additional work to be done on this concept
> paper and, certainly, they highlight an area which needs to be
> addressed. They conclude their commentary by saying that we need to
> get industry and FDA into a meaningful dialogue. I agree.
>
> Regardless of the ultimate form of this document, the OPS
> microbiologists remain willing and able to provide assistance to the
> development of the document.
>
> Thank you.
>
> DR. LEE: Thank you, David.
>
> Questions for David? If not, we have two more. Russ Madsen from the
> Parenteral Drug Association.
>
> **Industry Perspective**
>
> MR. MADSEN: Thank you. I wish to thank the FDA, all of the various
> divisions of FDA and groups within FDA and the advisory committee for
> inviting me to speak here this morning about FDA\'s new preliminary
> concept paper on sterile drug products produced by aseptic processing.
>
> \[Slide.\]
>
> You should have not overheads or slides, but you should have now in
> your packets the paper that was put together by the PDA Special Task
> Force. We, at PDA, know that it is very difficult to get documents as
> complicated as an aseptic-processing guidance to an approvable state.
> After all, we are in the business of writing technical monographs and
> reports and getting them approved by a diverse bunch of smart people
> with varying opinions.
>
> Those of us in industry in academia also serve on policy-setting
> committees and fight these battles every day. Therefore, we greatly
> appreciate the persistence and the effort the Agency has shown in
> producing this preliminary concept paper.
>
> Every time we publish a new PDA technical report, there are two
> criticisms. It is too specific and, guess what, it is not specific
> enough. We also appreciate the creativity the Agency has demonstrated
> in publishing this as a concept paper to further the dialogue among
> all interested parties.
>
> We are seeking this dialogue and we believe that it is essential to
> get the best possible work product. We applaud the fact that FDA has
> chosen to make the paper public at this time and we are excited about
> the next steps.
>
> \[Slide.\]
>
> PDA believes the concept paper provides guidance useful to
> pharmaceutical companies and FDA field investigators. The guidance
> should enable inspected firms to know what to expect during FDA
> inspections of their aseptic processing areas and eliminate
> observations based on hearsay, outdated guidance or expectations
> resulting from what other firms did to comply with arguably
> overzealous FDA 483 observations.
>
> There is a desire on the part of most individuals and companies to
> understand the aseptic-processing requirements and to comply. It is
> important that the final version is very clear on what types of limits
> and requirements are absolute requirements and what are suggestions
> where firms have the ability to make good scientific judgments based
> on the specifics of an operation.
>
> We appreciate that the document does have areas where the need for
> such judgment is respected. The concept paper supports the advantages
> of isolators relative to conventional manned aseptic processing. We
> believe this will encourage the use of isolation technology by firms
> that, having lacked guidance, delayed its implementation. It also
> provides the needed framework for open dialogue with FDA.
>
> Finally, the availability of new guidance should eliminate use by the
> field of draft guidance which is unavailable to the inspected firms.
>
> \[Slide.\]
>
> PDA\'s concerns are grouped into categories; best practices and cGMP,
> technical issues and unconventional terminology, scope and
> harmonization.
>
> \[Slide.\]
>
> Departures from current industry practices include media fills
> conducted in worst-case environmental conditions, environmental
> sampling of critical surfaces that are terminally sterilized, the fact
> that isolators do not normally employ unidirectional air flows or
> redundant HEPA filters and there was no evidence to support that
> isolators must be housed in classified areas.
>
> Further, the document goes on to say media fill should be conducted
> under environmental conditions that simulate normal as well as
> worst-case conditions of production. We believe media fills which
> already tend to be worst-case because of growth-promotion properties
> of the medium and the extra manipulation sometimes required should be
> conducted under environmental conditions representative of normal
> production.
>
> The document says that the monitoring program should cover all
> production shifts and include air, floors, walls and equipment
> surfaces including the critical surfaces in contact with the product
> and container closures. PDA believes that critical surface monitoring
> is not advisable because these surfaces are sterilized using validated
> processes. Monitoring these surfaces provides little meaningful
> information.
>
> If the results are positive, it could mean that the surface contained
> one or more microorganisms or that it was contaminated by the act of
> sampling, itself. Even if negative, the result may not be meaningful
> because of less than perfect recovery efficiency.
>
> Unidirectional air flow is generally unnecessary in closed isolators
> and the use of redundant HEPA or ULPA filters is not common practice
> and is unnecessary.
>
> Finally, with respect to the need to locate an isolator in a Class
> 10,000 or Class 100,000 environment, PDA believes isolators should be
> located in controlled but unclassified areas.
>
> \[Slide.\]
>
> Successful aseptic processing relies on strict adherence to specific
> well-defined procedures and on accurate knowledge of the critical
> factors that could result in nonsterile product if not properly
> controlled. Correct and consistent use of terminology with the
> industry and by FDA is critical to success.
>
> The section on air filtration indicates that hot-air sterilizer vents
> should be equipped with membrane filters. HEPA filters should be used
> for this purpose, PDA believes. The document says that particle counts
> in Class 100 areas should be taken normally, not more than one foot
> away from the work site. But the concept paper fails to define what
> the work site is leading to unnecessary ambiguity and inconsistent
> interpretation.
>
> The document says that air locks should be installed between the
> aseptic-processing area entrance and the adjoining uncontrolled area.
> Other interfaces such as personnel entries or the juncture of
> aseptic-processing room and its adjacent room are also appropriate
> locations for air locks.
>
> Typically, PDA believes that modern aseptic-processing areas are not
> equipped with air locks between the aseptic filling room and other
> portions of the APA. Finally, the terms alert limit and action limit
> should be changed to alert level and action level. Limits, we believe,
> are applicable to specifications while levels apply to process
> monitoring.
>
> Specification\--that is, limits\--relates to a direct measurement of
> product quality that is required to be met by an official monograph or
> filed application. Exceeding an alert or action level does not produce
> an out-of-specification result.
>
> \[Slide.\]
>
> While the concept paper provides guidance in many areas, two of the
> most important questions are not addressed; that is, regarding media
> fills, how many units should be filled and how many positives are
> allowable. Other questions which remain largely unanswered are can a
> media fill be an exact model of an aseptic-manufacturing process with
> predictive quality which can be challenged by going to extremes or is
> a media fill merely a demonstration that a manufacturer can
> aseptically fill a predetermined number of units under a given
> predetermined set of conditions without introducing detectable
> contamination.
>
> There is little guidance offered relative to performance of the
> remainder of the aseptic-processing area outside the critical zone.
> Many aseptic-processing operations have extensive areas that are
> either Class B 100 nonunidirectional or Class C, Class 10,000. This is
> where personnel are located. The document should include more detailed
> guidance in these areas, we believe.
>
> CIP/SIP technology; that is clean-in-place, sterilize-in-place
> technology. Although widely used today in aseptic processing, it is
> not addressed in the document.
>
> Finally, the concept paper fails to provide a systematic rational
> approach to aseptic process control and risk elimination. While
> buildings, personnel and components are discussed, there is no clear
> discussion about how the process should be set up and how the
> segregation of product and the environment should be accomplished at
> each step in the process.
>
> \[Slide.\]
>
> Commenting on the 1987 Guidance Document, PDA said, \"The PDA believes
> that the guidelines should include those areas of aseptic processing
> which are most likely to affect product stability, quality; namely the
> aseptic manipulations made by specially trained personnel during
> product handling and assembly. The physical means to sterilization
> employed by the industry have been validated to deliver sterility
> assurance level much greater than those which can be achieved by
> conventional aseptic processing.
>
> The body of technical literature available on the validation of
> sterilization processes is adequate and considerable and could simply
> be referenced by the guideline. We believe these comments apply today
> to the current concept paper. While the concept paper builds on the
> framework of the 1987 guideline, we believe it should be focused on
> aseptic processing; that is, the control and manipulation of sterile
> components, closures and containers and the control, monitoring and
> maintenance of the aseptic-processing environment.
>
> Subjects such as endotoxin control, equipment qualification and
> sterility testing are covered in the literature in great detail. If
> FDA believes better information about these subjects is needed, we
> believe separate guidance documents would be appropriate.
>
> \[Slide.\]
>
> Finally, it would be most helpful to know when the document is
> providing guidance, should, and when it is defining requirements,
> shall, as these terms are used most frequently in isodocuments. Table
> 1 and all references to room classifications refer to Federal Standard
> 209(e). EIST, assigned by the GSA as the preparing activity
> organization for Federal Standard 209(e) has recommended that
> International Standard ISO 14644-1 superseded Federal standard 209(e)
> which became obsolete November 29, 2001.
>
> The document goes on to say, \"Air in the immediate proximity is of
> acceptable particulate quality when it has a per-cubic-foot particle
> count of no more than 100 in size range of 0.5 micron enlarger, Class
> 100, when counted at representative locations normally not more than
> one foot away from the work site within the air flow and during
> filling and closing operations.\"
>
> We believe this section needs to be harmonized with EU requirements
> where sample size and limits are quite different. The document says
> that each individual sample result should be evaluated for its
> significance by comparing to the alert or action limits. Averaging
> results can mask unacceptable localized conditions. A result at the
> action limit urges attention to the approaching action conditions.
>
> The EU approach, on the other hand, is that environmental monitoring
> results should be averaged.
>
> \[Slide.\]
>
> Our recommendation are that the concept paper be reviewed by some kind
> of a committee, either an ad hoc committee of FDA Headquarters or
> industry or, perhaps PQRI, to resolve issues. The committee then
> submits the revised document to the FDA for review and approval. Final
> draft is issued for public comment and the revised aseptic-processing
> guidance is finally issued.
>
> PDA believes the document provides a good platform for a final draft
> guidance meeting the needs of FDA Headquarters, ORA and the regulated
> industry. In order to quickly develop a final guidance document, we
> recommend that the concept paper be reviewed by an ad hoc committee
> consisting of FDA Headquarters and field personnel as well as industry
> aseptic-processing experts.
>
> We believe that media fills are an important component in assuring
> aseptic-processing operations are under control. But, even when a
> media fill consists of filling more than 100,000 units over three
> consecutive shifts, a media fill cannot assure the sterility of the
> next or any other production lot. We need to break the mold and find a
> reasonable alternative to massive media fills.
>
> One possible solution would be to replace process-simulation tests or
> media fills with aseptic-process assessments or process-simulation
> evaluations in which the media fill would consist of a specified
> number of units\--for example, 10,000\--with a normal and atypical
> interventions running under normal line conditions with a specified
> acceptance criteria\--for example, not more than one positive.
>
> The media fill would be but one part of the aseptic-process assessment
> which would also include evaluation and documentation of environmental
> controls, environmental monitoring results, gowning procedures,
> employee training, room-pressure differentials, air-flow patterns and
> maintenance.
>
> The overall evaluation would provide a high degree of assurance that
> normal aseptic-processing operations result in products with high
> levels of sterility assurance.
>
> We look forward to working with FDA, industry and other professional
> associations to develop a world-class aseptic-processing guidance
> document.
>
> Thank you.
>
> DR. LEE: Thank you very much. Any immediate comments? Yes?
>
> DR. MOYE: I wonder if you could help me differentiate your concern
> about action limits and action levels. Could you say that again,
> please?
>
> MR. MADSEN: An action level, we believe, is typically used for
> something that is related to a process. It is not a firm
> specification, and exceeding a level merely indicates the fact that
> the process has drifted from its normal state or, for example, some
> action needs to be taken. A limit, on the other hand, we consider a
> firm specification. So exceeding a limit would cause a failure of a
> product, for example.
>
> Typically, a limit is something like the USP specification or some
> number filed in an NDA or other form of application.
>
> DR. MOYE: So, then, is your concern that the paper is inappropriately
> focussed on limits when it should be focussed on levels?
>
> MR. MADSEN: In some cases and, in other cases, we believe that the
> paper is not specific enough. It doesn\'t provide enough guidance to
> know where a firm needs to be in terms of its compliance stance.
>
> DR. MOYE: The action that is taken when a limit is exceeded should be
> different than the action that is taken when a level is exceeded?
>
> MR. MADSEN: Typically, when a limit is exceeded, it results in a
> failure of the product or rejection of the product.
>
> DR. MOYE: Thank you.
>
> DR. LEE: Thank you very much. Bear in mind that we need some
> volunteers to review this paper.
>
> The final presentation for this morning is from Professor Berit
> Reinmuller at the Royal Institute of Technology in Stockholm, Sweden.
> She will be talking about design, control and contamination.
>
> **Design, Control and Contamination**
>
> DR. REINMULLER: Good morning.
>
> \[Slide.\]
>
> This presentation, airborne contamination in clean rooms, design
> matters, is based on research by Professor Ljungqvist and myself at
> Royal Institute of Technology.
>
> \[Slide.\]
>
> Our research has shown that the contamination risk can be described by
> the impact vector. The impact vector is depending on the velocity and
> the concentration of contaminants. The numerical value of K is the
> number of particles passing a unit area for the first time. The area
> is placed perpendicular to the particle flow.
>
> \[Slide.\]
>
> In a unidirectional flow, the particle impact can be calculated. If we
> have a continuous point source of contamination in the unidirectional
> flow, the concentration and particle impact can be calculated with
> this equation. After proper simplification, we can see that it is
> proportional to velocity and concentration.
>
> \[Slide.\]
>
> Class 100 environments become contaminated and the contamination ends
> up in the product. Here is a cross section of a unidirectional-flow
> unit with side walls connected directly to the filter. How can
> contaminations in the room air be intrained into this zone.
>
> We have openings here and a flat surface perpendicular to the flow. If
> the surface is wide enough, we will have a stagnation region and the
> shape of the stagnation regions will depend on the size of the side
> walls, or the size of the opening. It is possible for room air to be
> intrained into the stagnation regions where contaminations move in an
> unpredictable way.
>
> This is of special importance if small vials are processed close to
> the working surface.
>
> \[Slide.\]
>
> Another case is shown in this cross section. It is a unidirectional
> flow unit where the side walls do not connect to the filter and the
> filter, the clean air, goes out here. If this opening is too small,
> then room air that is intrained into to clean zone can be dispersed
> all over the clean zone and can be stuck in the stagnation region.
>
> \[Slide.\]
>
> If we don\'t have any side walls at all, we will have an ingress
> region here where clean air and room air are mixed. We still have the
> stagnation region along the table and this situation is very sensitive
> to movements, movements of people, transport of material, doors that
> open, could cause ingress of room air in the clean zone and increase
> the risk of contamination of the product.
>
> \[Slide.\]
>
> This air movement you cannot see but visualization is an aid to
> understand the air movements. Here we have a unidirectional vertical
> flow unit. But, close to the horizontal surface, you can see the flow
> is horizontal. It sweeps along the bottle and, downstream, the bottle
> will have a way where contaminants are accumulated.
>
> \[Slide.\]
>
> Sometimes, the equipment we use in the clean zone\--here is a vertical
> unidirectional flow unit. We have a small stopper ball here. The air
> moves nicely here. But around and above the stopper ball, it is a
> stagnation region where contaminants are kept and it is a long cleanup
> period. Visualization is an aid but it is not enough for evaluating
> the aseptic processes.
>
> \[Slide.\]
>
> The LR method, the method for limitation of risks or similar
> approaches are very useful when evaluating aseptic processes and
> single interventions. The method is based on visualization of air
> movements to identify stagnation regions. A challenge test where a
> particle counter is placed in the critical area and simultaneously
> particles are generated outside or along interventions.
>
> A risk factor is calculated and the risk factor is the number of
> particles measured in the critical area divided by the number of
> particles in the challenge. When the risk factor is less than 0.01
> percent, less than 10^-4^ during the challenge test, then there is no
> risk of airborne contamination during ordinary operation conditions.
>
> \[Slide.\]
>
> I\'m sorry for the slides here, but this should be a unidirectional
> air flow. We have sterile bottles here and a cover should be placed on
> the bottles. This is to illustrate how to evaluate single
> interventions. The particle counter is set up close to the bottle
> opening. Particles are generated along the operator\'s arm and we
> compare manual operations placing the stopper on the bottle or using a
> tool placing the cover on the bottle.
>
> In manual handling, we have a number, about 1,000 particles counted
> close to the bottle, a risk factor of 10^-3^ and an identified risk
> situation. Using the tool, generating particles in the same way,
> measuring at the same place, we find fourteen particles here. So, by
> changing from manual to an operation working with a tool instead takes
> the risk situation away.
>
> \[Slide.\]
>
> A case study by comparing different feeding or accumulation tables,
> the filling lines are the same. Rotating a feeding table about this
> side, the particle sensor above the table, measured risk factor,
> 10^-1^, very high and that it was a bad design was confirmed by media
> fills.
>
> We had much, much more than 0.1 percent contamination. We had close to
> 10.
>
> A straight feeding table, the filing line exactly the same, the same
> particle sensor location above the table, the same generation of
> particles outside the accumulation table, and less than 10^-4^
> particles. Few particles measured and the risk factor less than 10^-4^
> and no risk, and the media fills were, in fact, zero on the same
> filling line.
>
> \[Slide.\]
>
> I hope you can recognize an ampule filling line. It is infed from the
> sterilizing tunnel. The vials go around, or ampules. They are filled
> and closed and go out of the filling room there. It is all covered
> with unidirectional flow.
>
> We tested the efficiency of the barrier. This is the filling line
> again from the sterilizing tunnel, the accumulation table. And then
> the filling zone. There are different doors here, one here. We placed
> a particle-counter sensor in the filling zone and then, in different
> spots along the line, generated particles outside above the doors
> wherever there was a small opening and below the side walls.
>
> We measured zero, zero, and suddenly, here, above this door, when
> particles were generated here, we found particle ingress of room air
> in this locations. When particles were generated here on the table
> where you push the buttons, we could also trace an ingress of room air
> to this. So, zero everywhere but two locations, two potential ways of
> ingress of room air. This didn\'t show on the media fills.
>
> \[Slide.\]
>
> So, to use the LR method or a similar approach improves the
> microbiological risk assessment. It is not depending on collection and
> growth of viable particles. It identifies dispersion routes of
> airborne contamination and it gives easy and easy-to-understand
> results.
>
> \[Slide.\]
>
> The ISO Class 5 operational status can be maintained in different
> ways. You can have tailor-made side walls. You can have restricted
> access barriers. You can have everything closed up in isolators and
> sometimes you need vertical separators along filling lines to prevent
> air movements and transport of contaminants along filling lines.
>
> \[Slide.\]
>
> Risk situations within the unidirectional flow are when obstacles are
> placed, and often we do place obstacles in the unidirectional flow. If
> they are close to the border of the critical zone, entrainment from
> room air can occur. Wakes and vortices are formed. Large horizontal
> tables, large surfaces, cause stagnation regions. If you are
> processing small vials, then this is a problem.
>
> \[Slide.\]
>
> If we look at what the ISO 14698 says about biocontamination control,
> it says that zones at risk should be monitored in a reproducible way
> and a formal system for risk assessment should be in place to control
> factors affecting microbiological quality of the product.
>
> \[Slide.\]
>
> So risk assessment of airborne contamination requires good knowledge
> about the clean-room performance. It requires knowledge about the
> process in detail and also knowledge about the airborne dispersion of
> particles. Particles with or without microorganisms are transported in
> exactly the same way.
>
> \[Slide.\]
>
> Some requirements on the filling equipment used in unidirectional-flow
> radials. The should be easy to clean and have an aerodynamic design,
> reliable mechanization in order to prevent unnecessary interventions,
> a certain ruggedness, simple orientation and unscrambling. It should
> not be necessary to build a filling machine of 96 parts in the laminar
> flow, unidirectional flow.
>
> If possible, it should have good ergonomics for the people working
> along the line.
>
> \[Slide.\]
>
> When risk assessment is performed in a proper way and the safety is
> measured and evaluated, then we can design safety into the process and
> the risk of contamination failures can be prevented.
>
> \[Slide.\]
>
> This is the most common contamination sourcing in clean rooms. But
> today\'s clean-room clothing, clean-room underwear, clean-room
> dresses, is much more efficient than it was twenty-five years ago.
>
> \[Slide.\]
>
> Aseptic production areas do not only consist of the filling room.
> There are the rooms around it. And we have flows between rooms,
> between openings. If we have constant pressure differences, then the
> pressure differences will cause a flow of air. For example, a
> sterilizing tunnel opening on a filling line and a pressure difference
> of 15 Pascal means that you will have a velocity of 5 meters per
> second through the tunnel opening. That air must be provided by the
> unidirectional flow above. Otherwise, room air will be entrained into
> the sterilizing tunnel.
>
> Small openings, an opening 20 centimeters in diameter, will give the
> same outflow, 5 meters per second if you have a 15 Pascal pressure
> difference, and a flow of about 4 cubic feet per second out of the
> room.
>
> One comment about the door. When you open a door, you lose the
> overpressure.
>
> \[Slide.\]
>
> When there are temperature differences, there are air flows. At the
> autoclaves, we often have temperature differences when the autoclave
> opens. Lyophilizers and sometimes at doors, doors between, for
> example, the changing room and the filling room, there might be
> temperature differences. When the temperature differences are four
> degrees or more, then the 10 Pascal overpressure cannot prevent
> ingress of air from the dirtier area into the cleaner one.
>
> \[Slide.\]
>
> This illustrates the case with the hot autoclave being opened. The hot
> air escapes here and room air is entrained here over the load. We have
> a 40 degree temperature difference, 40 degrees Kelvin. Then the
> opening of an autoclave, 1 by 1 meter, the flow in the autoclave and
> out of the autoclave is approximately 1 cubic meter per second.
>
> \[Slide.\]
>
> A decreasing temperature for the lyophilizer, if we have 25 degrees in
> the room, -2 degrees in the lyophilizer, it is a difference of 25
> degrees, then air will come this way. The cold air, when the door is
> open, will flow out and be replaced by air this way. How much air do
> you need to compensate for this? It can be calculated and you can
> predict, calculate, how large a flow you need here to protect the
> lyophilizer and to transport contaminations away from men working in
> front of it. It can all be calculated.
>
> \[Slide.\]
>
> If the autoclave looks like this, a huge high opening and let\'s say
> that 25 degrees will take in almost 1 cubic meter per second here and
> 1 cubic meter per second out. Instead, if there is a pit opening 20
> centimeters high and the same width, 1.6 meter, the flow will,
> instead, be 1 cubic foot per second. So the difference here in the
> opening size affects the volume of the flows.
>
> \[Slide.\]
>
> There is a need to assess the situations of airborne contamination in
> a scientific way and design certainly matters.
>
> Thank you.
>
> DR. LEE: Thank you very much. Are there any questions? If not, there
> is some food for thought. You have the concept paper in front of you.
> You have the background behind this concept paper. You heard the
> presentations that help you to analyze this paper and engage in some
> lively discussions after lunch.
>
> So, if there are no other questions, I propose that we adjourn until 1
> o\'clock when we have the open public hearing. I think there are six
> individuals. You know exactly who you are, what your order is and how
> much time you have and I will be watching the time very closely.
>
> Are there any remarks from the administrative side? If not, thank you
> very much and I will see you back at 1 o\'clock.
>
> \[Whereupon, at 11:38 a.m., the proceedings were recessed to be
> resumed at 1 o\'clock p.m.\]
>
> A F T E R N O O N P R O C E E D I N G S
>
> \[1:00 p.m.\]
>
> DR. LEE: The next item is the open public hearing. I have six
> individuals. Please excuse me if I pronounce your name incorrectly.
> Let me go by the first name. Maybe that is easier. Ken? Ken, you have
> five minutes.
>
> **Open Public Hearing**
>
> DR. MUHVICH: I recognize the importance of this concept paper and it
> is important for the FDA and the industry to get together and get some
> consensus now rather than later. However, I would like to focus on
> something that I think everyone is missing. If it is not the elephant,
> they are ignoring it anyway.
>
> Aseptic technique in this industry is, sad to say, not very good. If
> the industry does their job and the FDA does their job, then that will
> provide a lot in the way of sterility assurance for the products that
> are being put out on the street. Because of the nature of cGMP these
> days and the quality of systems inspection and so forth, much time is
> spent by FDA investigators in conference rooms looking at stacks of
> investigations to see if people are doing a good job with that and
> little time is spent watching filling operations to discover that
> aseptic technique is not what it should be.
>
> I learned aseptic technique as a young corpsman in the Navy on a
> hospital ship in Viet Nam. If the aseptic technique\--if I had the
> kind of aseptic technique then that people have in clean rooms
> nowadays, the OR nurse would have smacked me in the head and sent me
> away until I could come back again.
>
> People always talk about retraining in this but there is no guidance
> in the industry\--I just want to make the point the supervisors in
> clean rooms are not doing a good job at all. They are there. They
> observe people with breaches in aseptic technique and they do nothing
> about it.
>
> Aseptic processing and aseptic technique have to be 100 percent every
> day. There can\'t be a day taken off or then you are going to have the
> types of things that Rick Friedman was talking about earlier.
>
> I recognize the value of this guidance document but I think people
> need to refocus\--I didn\'t hear anybody mention the word aseptic
> technique today and it is typically not mentioned anywhere. But the
> key to aseptic processing is proper aseptic technique. There aren\'t
> any people that I see, or very few people, I should say, that really
> know what it is and how to teach it and it is a big problem for this
> industry, as I see it.
>
> Thank you very much.
>
> DR. LEE: Thank you, Ken.
>
> Any questions for Ken? David Miner who actually was my bodyguard from
> the hotel to here this morning.
>
> MR. MINER: Little did I know how exciting it was going to be walking
> over here from the hotel this morning. I am Dave Miner. I am with Lily
> and I am speaking on behalf of PhRMA and I am going to echo things you
> have heard several times already.
>
> We do believe firmly that good science-based GMP guidance could
> provide important advantages for all stakeholders in this process,
> better assurance of quality products for consumers, companies less
> likely to make mistakes and allow FDA to focus on the truly gray areas
> and the areas where things are changing or need to change instead of
> things that should be common accepted standard practice.
>
> In that light, we welcome the concept paper and the release of the
> concept paper. We know that significant effort has gone into carrying
> it this far. New guidance is desperately needed in this particular
> area and it is a positive step to publish a draft.
>
> As you heard a bit from Russ and I am sure there will be many other
> comments going forward, this draft needs significant improvement. But,
> folks; that\'s normal. That is where is should be. That is part of the
> process of getting the good guidance is putting something out there
> and having a dialogue around it and talking about it.
>
> So we should feel very good that we have it out there. Hopefully, many
> of things, as Rick talked about this morning, that are already
> included there are positive steps. Some others are going to need
> adjustment, but that is part of the process.
>
> Which brings me to the importance of process. I believe, really, to
> get good GMP guidance you have got to have good process. If you don\'t
> have a good process, number one, it will never get out. Number two, it
> has no chance of being timely. This is an area that is moving too fast
> for us to wait five to ten years to get something out. By the time you
> get something out in five or ten years, it will have changed on you.
>
> So good process is really critical going forward. I think that process
> is most likely to be rapid, effective and provide cost-efficient gains
> in product quality over time if it comes to an active dialogue with
> industry, academia and regulators all talking.
>
> We, in industry, have long been criticized and criticized ourselves
> when people in discovery research took a compound and \"threw it over
> the wall to development,\" or development took a product and threw it
> over the wall to manufacturing. A very valid criticism.
>
> The same applies when you think about guidance. You really need to
> have folks talking to each other in real time to think through what
> are the best ways to do things.
>
> So, in that light, we wonder, can the progression of the concept paper
> and the draft guidance to follow perhaps serve as a pilot for a better
> process. Can PQRIs serve as a key incubator for this better guidance.
> PQRI brings those key parties together. We would like to see PQRI
> tackling key aspects of aseptic processing among the technical experts
> that need to be brought together.
>
> Specifically, on the concept paper, I am not going to comment, with
> just one exception, and that is that the importance of the regulatory
> system, not just guidance but all aspects of the system, encouraging
> positive change. Take, for example, the use of isolators. There is
> general agreement that a well-designed isolator can provide
> significant improvement over conventional aseptic processing.
>
> This is, in fact, reflected in the opening part of the concept paper
> and there is new section, Appendix 1, on isolators. However, when you
> think about the system, to date, the regulatory environment in the
> U.S. appears to actually have discouraged the introduction of
> isolators, if you look at the update of isolators in the U.S. as
> compared to the update in Europe.
>
> So, we need to very careful and thoughtful about how we regulate so
> that we encourage good change.
>
> Let me just pick out one example. It is a very small one, but just as
> an illustration of how we need to be careful. Line 1458 in the
> Appendix I calls for a six-log reduction of BIs on the inner surfaces
> of isolators during their decontamination.
>
> By contrast\--this is the case of isolators where we should be having
> better protection\--there is no such requirement for the less
> protective conventional aseptic processing environment. So you have
> moved to a more protective environment and you have added a new
> expectation. Why is that potentially a problem?
>
> The cycle times that are required for vapor-phase hydrogen peroxide to
> get to that level of decontamination, maybe you have to increase to
> realize that. You might be confident that all the surface areas that
> you happen to have inside that isolator are going to get there which
> may cause your management to question the viability of the project and
> whether you should be going forward with it at all.
>
> This one requirement, being a new requirement, has the potential,
> along with other things, to discourage what I think we all would
> agree, when it is done right, is good change. So we just raise that as
> a cautionary note about thinking through how this will encourage good
> change, which we all need.
>
> So, to conclude, PhRMA applauds the release of the concept paper and
> we look forward to looking with the Agency as it drives forward to
> final guidance.
>
> Thanks.
>
> DR. LEE: Thank you. Questions for David?
>
> DR. KIBBE: I have a couple of questions, since you are the industry
> and standing there smiling at me. We saw some recalls on that bar
> graph which interested me, that there was such a big dramatic jump. I
> know you can\'t answer why all those were recalled but, just out of
> curiosity within your own shop, when you have a batch failure, is it
> more often a sterility problem or more often something else.
>
> MR. MINER: I am not sure I can answer that question off the top of my
> head, but one thing to think about is how many aspects, and Rick
> talked about this this morning\--how many aspects do you have to
> control when you are talking about an aseptically processed product.
>
> So if you think strictly in terms of the number of systems that you
> have to control and the potential for something to go wrong, your odds
> are greater just because of the number of things that you are trying
> to control. I can\'t quote statistics off the top of my head.
>
> Now, I would say, with regard to that recalls thing, I think it would
> be helpful to look behind that as you try to get to root-cause
> analysis for any problem that you run into, and understand what are
> the factors that are driving that, what led to the circumstances where
> you had those recalls and pull those out, each and every one that is
> significant in there.
>
> DR. KIBBE: But you don\'t have any sense of\--what I am really getting
> at is how often do we say, okay, we are not going to release this
> batch because we know that there is a problem or that we think there
> might be and we can\'t prove it one way or the other.
>
> MR. MINER: Oh, that definitely happens. Without the appropriate
> documentation, you can\'t go forward and release the product against
> the risk of somebody questioning whether\--even if you thought it was
> all right, if you don\'t have the documentation, you can\'t release
> that product.
>
> DR. KIBBE: Thanks.
>
> DR. LEE: Thank you.
>
> The next person is Professor Ljungqvist from Sweden.
>
> PROFESSOR LJUNGQVIST: Good morning.
>
> \[Slide.\]
>
> A microscopic vortex in a clean room is a fact. What do you know about
> vortices? Well, they will accumulate contaminants.
>
> \[Slide.\]
>
> That has been proved as well in theory as in practice experimentally.
> Here you can see the theoretical equation and, if you are smart
> enough, you see the concentration accumulation.
>
> \[Slide.\]
>
> But that is not so easy, so I show a smoke filter instead. Every photo
> is taken with intervals of a couple of seconds. You can see that
> accumulation effect of the vortex. What you should be aware of,
> vortices will accumulate contaminants.
>
> \[Slide.\]
>
> Laminar air flow is cold in the draft but it should be unidirectional
> according to my opinion. Here you have laminar air flow when you see
> particles follow the stream line all the way. Here you have turbulent
> air flow when you have the small fluctuations around. Most Class A
> environment in the pharmaceutical industry has a parallel flow like
> this. So the right wording which I use should be unidirectional air
> flow and skip laminar flow.
>
> \[Slide.\]
>
> If you have obstacles in unidirectional air flow, and it is a low
> velocity, it will, in the beginning be a smooth stream line, smooth
> air patterns. But if you increase the velocities, you first will get
> wake vortices and, after that, vortex streets. If you increase the
> velocity more, you will be a high range of turbulencies.
>
> \[Slide.\]
>
> Here we have a practical case. You have a filter fixture here. First,
> you get the wake vortices and then the vortex street. In this case,
> you also get irritational vortices. By the way, you can see a filter
> down here in the critical region of such a vortex.
>
> You are discussing, in the draft, about the sweeping action. That
> means that this should take away these contaminants in this region,
> also. You also write in the draft that one should measure at this
> level and then you said \"or\" at this level. I think it is very
> important that you measure also velocities in those levels.
>
> So, in Line 257, an \"or\" should be changed to \"and\" because you
> should measure as well up here as down here.
>
> \[Slide.\]
>
> Here, if we have a person in a unidirectional air flow\--in this case,
> it is a horizontal unidirectional air flow. You see the smoke source
> here and it goes out very smoothly. The air goes like this passing the
> person. Everything is okay.
>
> \[Slide.\]
>
> What would happen if the person raises his hands and arms? Then you
> get a sudden change of the pattern. In some cases, that can be very
> dangerous for the product or the man.
>
> \[Slide.\]
>
> Here is a horizontal unidirectional air flow unit. Here we have the
> HEPA-filtered air and the main direction of the air movements is like
> that. Here we have the smoke source and you can see how the smoke goes
> from this region and out in the ambient air which is the intention, of
> course.
>
> But even if you have some bottles here and you have the smoke source
> here, it will go, not out. It will go back because of the way it
> vortices up to the critical region and then out.
>
> \[Slide.\]
>
> Still, we have a main air flow out like this and the smoke source
> here. But you move your hand like this and then the contaminants will
> follow from the person into the critical region.
>
> \[Slide.\]
>
> In this case, you have the vertical air flow and the machinery. The
> moving machinery will also give disturbances, wake vortices, et
> cetera, and you see the complex and rather difficult situation in this
> region.
>
> \[Slide.\]
>
> I would only like to say the part in the draft be Lines 272 to 282
> stresses the importance of knowledge about personnel movements which I
> think is important that we can read it there.
>
> I have five minutes. After having heard Dr. Reinmuller\'s and my
> presentation, you can understand, see immediately, of course, that
> this picture does not show good aseptic conditions, if you are
> trained, of course.
>
> Thank you very much.
>
> DR. LEE: Any questions?
>
> MR. MUNSON: If you take your velocity measurements down basically at
> work height or whatever where the vortexes are, how do you get
> accurate readings?
>
> PROFESSOR LJUNGQVIST: First of all, you shall not have that vortex
> system. If you have it, you don\'t get accurate. But you should have
> smoke visualization telling you it is not accurate.
>
> MR. MUNSON: Okay.
>
> PROFESSOR LJUNGQVIST: But if you get a sweeping action, you should be
> able to measure that and get an actual value because, with the
> sweeping action, you have the main flow direction and that main flow
> direction is capable to be measured. But, of course, you also see it
> with your smoke visualization. But I think you shall do both.
>
> MR. MUNSON: Right. It has just been my experience that when you get
> down that\--it gets very, very hard to get good readings because of
> the direction of the air.
>
> PROFESSOR LJUNGQVIST: You should look at it. If you take that away, no
> one\--I know that persons in the Nordic countries, they put an \"or\"
> there. That means that we don\'t need to bother. I will have the
> \"and\" because they should bother with that region.
>
> DR. LEE: Thank you very much.
>
> Mr. Becker from Merck.
>
> MR. BECKER: Good afternoon, everyone. My name is Martyn Becker and I
> am here representing Merck and Company. I would like thank you all for
> giving me the opportunity to put forward the views of Merck on the
> document that has been published now by FDA, and thank you very much
> for that.
>
> The document does provide good basic philosophical guidance for
> aseptic processing. What I would like to just put before you are some
> opportunities for clarification which exist within the document.
>
> We think that there are concepts that would be beneficial to enlarge
> including qualification of the scope of processes that are referred to
> in the paper, specifically enlargement upon guidance that is given in
> the document. I offer some examples; references to limited aspects of
> bulk processing. The document indicates that it only applies itself in
> a very limited fashion to bulk processing
>
> So the important points of some of the thought processes are not
> references; for example, aseptic processing of bulk materials post
> final sterilization and the use of true closed systems.
>
> There is a section on isolators, but it doesn\'t reference the use of
> different types and specifications within the industry. The relevance
> of the guidance to classes of pharmaceutical products that are not
> required to be sterile according to filing or usage but are processed
> aseptically because of the nature of the product. I am referring to
> things like oral vaccines here.
>
> It would be beneficial to make sure that the terminology used is
> consistent throughout the document so that concepts contained in the
> paper can be most effectively realized\--one of the biggest examples
> is a reference to ISO 14644 that you have already seen\--which do not
> appear to harmonize with what is now obsolete in terms of Federal
> Standard 209(e) and the references throughout the paper are in the
> Federal Standard terminology.
>
> The industry hoped that there would be some kind of steps towards
> harmonization of area classifications with regard to the European
> Annex 1 classifications and ISO 14644, especially since it has been
> stated within the revision of the Annex I, the European Annex I,
> process that it is intended to harmonize with ISO 14644 for a
> particular specification.
>
> We fully support the use of a science-based approach for the areas
> with in the concept paper although there are a number of these areas
> which are unclear. There is some sort of confusion, I think, with the
> table on Page 3 in terms of area classifications which appear to
> simultaneously refer to a less than 3 CFU limit for Class 100 which is
> immediately, then, modified by the statement that there should be
> normally no contamination.
>
> It is not clear what the reference to 1 in 1000 units is within the
> process-simulation section. It is not clear what this is meant to
> convey. It is agreed that the use of inappropriate statistics is not
> meaningful for simulation acceptance, but it should be acknowledged
> that what is essentially a sampling process, within that process,
> there should be some sort of defined mechanism to apply the sample to
> the whole population of the simulation.
>
> Also, you could cite things like filter-integrity testing with regard
> to the intent or the expected criteria, specific examples being the
> guidance\'s relevance to hydrophobic vent filters, or the requirement
> to test depyrogenation tunnel filters in in-use conditions, which
> could be a safety issue as these might be up to 300 degrees Celsius.
>
> Process-simulation requirements focus upon the simulation of the
> actual process and yet the extremes of the temperature and humidity
> are required which is not representative of the process as carried
> out. There is also no indication of what worst-case environmental
> conditions actually means.
>
> A very important point is container-closure integrity which is
> important with regard to the aseptic-process validation, but there is
> very little reference to it. If it is required that another guidance
> document be referred to, then we would recommend that it specifically
> be referred to in the back of the document.
>
> Isolator-background classification requirements are also unclear for
> all isolator types since it might be inappropriate to apply
> environmental criteria for open manufacturing isolators as well as
> closed testing ones.
>
> In summary, we acknowledge that regulatory documents are not normally
> over-prescriptive but rely upon the use of good science to make sure
> that sound justifications exist for the rationales used. We would
> support additional editorial input to assure a consistent
> implementation and the interpretation of requirements. Also, we
> support the assurance of the guidance process by supporting effective
> training of field investigators that will eventually be responsible
> for implementation of this guidance when it becomes a guidance
> document.
>
> Lastly, it is our opinion that for such a document of such fundamental
> importance to the aseptic-processing industry worldwide, an
> appropriate review periods, say 90 days, would be at least appropriate
> for its review and full comment.
>
> We support the manufacturing-subcommittee incentive. It is very
> beneficial in view of the global regulatory environment worldwide.
>
> Thank you very much.
>
> DR. LEE: Thank you.
>
> Any questions for Marty? Very clear. Thank you. Maurice Phelan?
>
> MR. PHELAN: Thank you. My name is Maurice Phelan and I am here on
> behalf of Millipore Corporation primarily to thank the FDA, all of the
> FDA participants, in producing this document and the members of the
> committee for what has been a long way to document, I believe.
>
> In particular, we would like to thank you for the inclusions. From
> talking to some of my colleagues and some of our industry partners,
> the rider inside of that document which really sort of tells us that,
> for things like introductions of new technologies, there is clearly,
> from our point of view, the latitude to implement new technologies
> assuming that there has been appropriate validation conducted around
> those and that, to us, is very important given some of the programs
> which we have in place to help this industry in the area of aseptic
> processing.
>
> We understand, by the way, truly understand, that filters are a very,
> very small part of an aseptic process. But, to Ken\'s point earlier,
> filters work very well. But, if they are not connected properly, if
> good aseptic technique is not used, they probably won\'t do as well as
> one might think, not the fault of the filter.
>
> \[Slide.\]
>
> Just one area which I believe we are going to further comment on, and
> by the way, as an organization, and personally, we would be delighted
> to participate in any review processes that result from the decisions
> of the committee or this meeting\--rapid-transfer technology is
> referred to on Page 37, aseptic processing and isolators.
>
> We intend to put forward some data as well as a discussion on the fact
> that there is a clear differentiation between decontamination,
> transfer and the ability to sterile-transfer through an appropriate
> port using sterilization sources such as UV technology 254 and UV.
> That assumes, of course, that the appropriate, well-thought-out and
> demonstrated validation package associated with that sterilization
> source can pass along with it.
>
> We are currently working on some data in that regard to support some
> of the comments that we are going to make, but we believe that
> technologies like this primarily benefit this industry in the area of
> removing personnel ingress, particularly in the sterile-isolator area.
>
> \[Slide.\]
>
> Moving on, briefly, to the filtration portion and, in fact, the
> filtration-efficacy portion of the concept brief, Page 21, there is a
> discussion of porosity of filters and pore-size ratings. This is
> really a semantic issue but the statement where 0.2 micron are
> smaller, if that were literally processed, it would, in fact, rule out
> something like a 0.22 micron rated filter.
>
> That is not really the issue so much as I think there is an
> opportunity to have a discussion around decoupling pore-size rating
> and sterilizing-grade efficiency and, potentially, to open a further
> discussion where we talk about sterilizing-grade filtration as a
> function of the validation studies that have been performed around the
> process and the individual filtration step and not the nominal rating
> of a filter.
>
> To that end, we would be inputting and further commenting on methods
> for validation of filtration efficacy building on some of the
> technical reports that are being produced by the PDA along with and to
> the point of the gentleman who spoke before me from Merck and
> validation of integrity-test methods for hydrophobic vent and gas
> filters and, of course, liquid-sterilizing grade filtration.
>
> Lastly, although the concept brief does allow for the discussion of
> endotoxin removal by membranes, there are some technologies,
> membrane-based technologies, in particular charged membrane
> technologies, which will remove very, very efficiently endotoxin from
> liquid streams and, although there is a lot of latitude in this
> document, as Rick Friedman pointed out this morning with the
> fifty-three broader statements where the word \"appropriate\" is used
> and generally is used, it may well be worthwhile having a discussion
> around that during the comment phase.
>
> That is really all that I would like to say this afternoon. Thank you
> very much and, again, we would be delighted to be involved in any type
> of further processes that will help put our expertise together with
> your expertise to produce a great document.
>
> Thank you.
>
> DR. LEE: Thank you very much.
>
> The final presentation is by Dimitri.
>
> MR. WIRCHANSKY: Good afternoon. My name is Dimitri Wirchansky.
>
> \[Slide.\]
>
> I am a pharmaceutical technology specialist for Jacobs Engineering in
> Conshohocken, Pennsylvania. I also happen to be the Isolation
> Technology Interest Group leader for PDA. In the beginning of the
> year, PDA put out a survey for the use of isolators and we wanted to
> find out how the industry was using isolators.
>
> \[Slide.\]
>
> The results of this survey were presented at an Isolation Technology
> Conference by PDA April into May of this year. Rick Friedman asked me
> if I would come to discuss a couple of the results of that survey as
> it relates to the sterilization or, rather, the decontamination of the
> isolator background. Also, I have addressed a few comments to Appendix
> I dealing with isolators.
>
> The survey was sent out. We got fifteen respondents. This slide shows
> the different applications of those respondents.
>
> \[Slide.\]
>
> I picked out the ones that I thought were most appropriate, that being
> sterility testing and manufacturing. We had fourteen respondents for
> sterility testing. Most people were doing sterility testing. One
> response was for some specialized testing.
>
> \[Slide.\]
>
> Of those respondents, two reported a decontamination to a 3-lot
> reduction. Ten reported a six-log reduction and one reported a
> sub-cycle, 10^-6^, which really went to 10^-12^. Then there were some
> other comments around 10^-6^. So, if you look at it percentagewise,
> you have about 14 percent on three-log reduction, 71 percent for
> six-log reduction and 7 percent for that double-kill cycle.
>
> \[Slide.\]
>
> This looks at aseptic manufacturing and the applications include
> formulation, low-speed filling, higher-speed filling and some other
> more specialized applications.
>
> \[Slide.\]
>
> In this case, one respondent reported a five-log reduction. Six
> reported a six-log reduction. Then there was another comment around a
> total deactivation of BIs, 10^-6^, which I counted as a six-log
> reduction. Then we had one other application using a three-log
> reduction for wrapped presterilized components or tubs and these are
> probably the presterilized syringes. That was a three-log reduction.
>
> So we have 11 percent for a five-log reduction, 78 percent for a
> six-log reduction and 11 percent with a three-log reduction for that
> specific application. As I say, the idea behind this was just to get
> an understanding of how people were using the decontamination process
> in the isolators.
>
> \[Slide.\]
>
> The introduction to Appendix I; I think coming out and saying the
> well-designed positive-pressure barrier isolator is better than
> conventional aseptic processing, I thing that is a very good thing to
> say because I go out and I help people design and build pharmaceutical
> plants. Some clients will come to me and they will say, \"Okay; we are
> going to build a new aseptic operation. I want to use isolation
> technology in this application,\" and so on.
>
> Other clients will say, \"I don\'t want to use isolation technology in
> this application,\" because, basically, they are afraid that if they
> make that decision, by the time they get their assets producing that
> they will have spent a lot of extra money and wasted a lot of time and
> they have a concern in that area.
>
> I think that a statement like this at least shows that the Agency is
> trying to be supportive of this technology and help advance the
> technology. We also have clients that aren\'t quite too sure whether
> they want to go towards the isolator or to go to some form of a
> modified conventional technology.
>
> I have been working in aseptic manufacturing since \'71, so I am kind
> of getting to be an old guy, but I haven\'t really seen anything that
> has made an impact in aseptic processing the way isolation technology
> has. So I think, as a leader of the Isolation Technology Interest
> Group, it is my goal to try to foster the advancement of this
> technology in good applications throughout the industry.
>
> \[Slide.\]
>
> These comments kind of refer to some specific items about the
> isolators. I didn\'t try to be all-inclusive but just to get a flavor
> for what I see for some of these things. Glove integrity; this is
> Section A.2. There are some strong comments. \"With every use, gloves
> should be visually evaluated for any macroscopic physical defect.\"
> You can read the rest of what is up there.
>
> This is true. If you have a noticeable tear, that is a problem. Where
> you get to have an issue is like what if it is not noticeable. Then
> you may find it later or how do you deal with this. People that use
> isolators are concerned about this.
>
> I think that the statement in the proposed regulations focusses very
> much on the gloves. That is important because gloves are important.
> But I think it should be part of a comprehensive operating and
> maintenance plan for the isolators. I think this plan should include
> measure to minimize the risks posed by the glove such as under-gloving
> or over-gloving.
>
> Proper aseptic technique requires the use of a sterilized implement
> such as forceps or some other thing for the intervention to critical
> sites. Basically, you shouldn\'t be sticking your gloved hand, even
> though it is an isolator glove, into the aseptic part of the process.
>
> During discussions at the Isolation Technology Interest Group, the
> users were very concerned about gloves. Different companies have
> developed different strategies, putting on gloves over the\--the
> operator would put a sterilized glove over the hand that went into the
> glove. One company talked about how they sanitized the inside of that
> glove.
>
> Of course, they decontaminated the outside of the glove as part of the
> decontamination cycle for the isolator. One company also talked about
> putting a glove over that glove sort of like to protect the isolator
> glove. So, the people that are using these things care about that and
> it is a concern for them.
>
> I think it is a valid concern. I just think that it has to be looked
> at as part of the whole because, if somebody is doing a procedure to
> try to minimize the risk of the glove, that we should look at that as
> part of the whole procedure and not just say, \"Oh, well; there is a
> hole in the glove. What does that mean?\" Has that glove been tested
> afterwards? Has it been plated? Do we find counts there, those types
> of issues.
>
> \[Slide.\]
>
> This one describes air flow. I think we have had two people already
> discuss air flow quite a bit. Where it says, \"In most sound designs,
> air showers over the critical zone once and systematically
> exhausted,\" this pretty much describes a unidirectional-flow
> isolator. Those typically find application in aseptic filling.
>
> Turbulent-flow isolators also have application, perhaps more in
> formulation with or without containment because sometimes we make
> aseptic products that are contained, especially on the formulation
> side, you may have a turbulent-flow isolator. So I think it depends on
> the application and what you are trying to accomplish.
>
> \[Slide.\]
>
> Clean-air classifications; 10,000 for Class 100,000, background for an
> isolator. From an operational standpoint, when somebody says Class
> 10,000 area to me, I translate that into a Grade B area with air
> locking and gowning and everything else. When somebody says, \"Do you
> think it is a good idea for me to put an isolator in a Grade B area?\"
> I say, \"Boy, that is the worst of both worlds,\" because an isolator
> is as fairly complicated piece of equipment.
>
> If you want to do an isolator right, it has to be integrated
> functionally with the operation. You have air systems to integrate.
> You have decontamination systems to integrate and then you have to
> interact with it through gloves or through RTPs and all this other
> kind of stuff.
>
> If you put that in a Grade B area so somebody is in full aseptic, you
> are making it much harder to do that. Then it is like why do you have
> an isolator. So I kind of think that is a design nightmare and I know,
> if I were the operator in that area, I don\'t think I would like that
> very much whereas, if the operator is more comfortable and can
> interact with the equipment, I think you stand a chance of getting a
> better result.
>
> I didn\'t address those comments just to air classification because,
> in some cases, if somebody has an older-style isolator, there may be a
> reason why they have that in what they may call a 10,000 air class.
> But I think a Grade C or a Grade D area, that Class 100,000 should be
> adequate for a production isolator especially if you consider that
> sterility-test isolators have been operating with excellent results in
> controlled nonclassified areas.
>
> \[Slide.\]
>
> Section C.1 talks about RTPs. I think, if the RTP is properly
> maintained, it should not cause an increase in contamination. However,
> you may want to limit interactions for process reasons. Like it is a
> lot easier if you can put a big container that will take a
> shift\'s-worth.
>
> \[Slide.\]
>
> I would like to get to one more, the decontamination. This is a
> six-log reduction. It is Section D.2. I think it depends on the
> isolator and the equipment inside. If you have stopper bowls and
> tracks that cannot be sterilized without opening the isolator, then I
> think it is a prudent thing to go for a six-log reduction. However, if
> you have an isolator that is used for handling presterilized
> components, I think a three-log reduction is adequate. So I think it
> depends on the application.
>
> If my time is up, that\'s fine. There is only one more anyway.
>
> DR. LEE: Thank you very much for studying the document so carefully.
>
> MR. WIRCHANSKY: I do want to thank you for inviting me because I think
> it is important. Aseptic processing is very important and the idea of
> revising the guidelines is a chance for everybody to normalize
> expectations and raise the level in the industry. I just hope that,
> through these interactions, the agency will consider both the
> theoretical goal of raising the standards and also the practical
> applications of what people have to do when they work in these areas.
>
> Thank you very much.
>
> DR. LEE: Is there a question?
>
> DR. BURSTYN: I have one question for you relative to the data you
> showed with the large number of manufacturers who are using a 10^6^
> kill, especially in light of the recommendation in PDA Technical
> Report 34 that talked about a three-log reduction. Can you speculate
> how much of that is really due to the lack of guidance and if it is
> somewhat a self-fulfilling prophecy where people are speculating on
> the 10^6^ level based on, perhaps, Agency Issues 483s, or what may be
> a perception of what is expected by the Agency and other regulatory
> authorities?
>
> MR. WIRCHANSKY: I think there is that concern that the client
> companies, or the people that I talk to, they want to get their
> processes approved. So, if they think that if they go a certain way,
> that their approval will be delayed six months or a year, they will
> probably weigh that against the extra work to do what they think is
> needed to satisfy the Agency.
>
> On the other hand, it depends on what is going on inside the isolator.
> I used the example of the stopper bowls and tracks because that is a
> part that directly contacts a product-contact surface. That is why I
> used the word \"prudent.\" I think it is prudent to decontaminate
> those parts to a 10^-6^.
>
> But then I used, on the other side, if you have presterilized
> components, then essentially the bioburden should approach 0, when you
> put them in an isolator and then you do a decontamination, you
> probably just take an extra cycle or just\--you are overkilling to
> what level when you have something that was essentially sterilized in
> the first place.
>
> That is kind of where I was coming from on that.
>
> DR. LEE: Thank you very much.
>
> That concludes the Open Public Hearing. The next agenda item is on
> Manufacturing Issues Discussion.
>
> **Manufacturing Issues Discussion**
>
> DR. LEE: I think the format is there will be four presentations.
>
> MR. FAMULARE: We have the question-and-answer session, actually, of
> the discussants on the agenda.
>
> DR. HUSSAIN: The plan is to have FDA folks come and state the
> questions and focus the discussion on the questions we have posed.
>
> MR. FAMULARE: The first person who will be discussing the issues would
> be Kris Evans on sterilization options, an FDA investigator.
>
> MR. FRIEDMAN: The agenda was actually supposed to include a discussion
> from the expert guests for twenty minutes followed by, then, Kris
> Evans\' presentation..
>
> DR. HUSSAIN: Vince, what that was, we were hoping the invited guests
> that we have, before Kris comes in, to sort of focus the questions, we
> would like to hear from them, the invited guests on their specific
> issues.
>
> DR. LEE: Does everybody have the agenda? There is a big gap. That is
> why I was puzzled. So we have twenty-five minutes for discussion and
> we don\'t have to necessarily have formal presentations, just
> discussion.
>
> DR. HUSSAIN: In a sense, I think what we would like to hear from the
> experts we have invited is their views on the concept paper and the
> questions that we have posed. Since we have twenty-five minutes, we
> have more time and we can use that time for them.
>
> DR. LEE: So now it is clear. Mr. Munson.
>
> **Discussants**
>
> MR. MUNSON: I think many of the concepts and the issues that have been
> brought up before are still relevant. I do concur that, in some areas
> of the document, there needs to be more definition. I think media
> fills is a very, very large part of that. People are going to want to
> know specifics, how many to fill.
>
> The issue of interventions is an extremely complex issue right now
> where I have to take 50,000 units worth of interventions and cram them
> into a 10,000 unit media fill which now really starts to make it look
> like I am validating something other than what I do normally.
>
> I think this is something where there needs to be some balance. As you
> read the guideline right now, I have to take a full batch-worth of
> interventions, both number and type of intervention, and put those
> into my media fill. If we go with the concept that I am trying to
> validate what I would apply to a product, now I have deviated even
> from that and I have got something that has twice the interventions,
> or three or four times the interventions per number of units that I am
> producing.
>
> It has also caused everybody to kind of go into some of the very
> weirdest media-fill processes where I have got some people that fill a
> few units and then do nothing and then fill a few more, and then do
> nothing. Then you have got the other kind that I fill some units, then
> I fill water units, then I go back to filling media, then back to
> water.
>
> There are all sorts of permutations that are out there. I think it is
> really getting quite confusing so I think this is something where the
> guideline I think needs to be a little more specific and maybe
> reevaluate what it is we are trying to do.
>
> We are trying to show the media fill and the process simulation is
> basically supposed to say that the process that I am going to supply
> to the product is capable of rendering a sterile product which is the
> product and the intent of doing this. So I think the process should be
> that I am going to do the normal number of interventions.
>
> The number of units filled I think should be\--you can come up with
> some function of what the batch size is because some processes, such
> as blow-fill seal, batch sizes can be 3 to 500,000 units is a batch.
> To do 5,000 units, this means I run the machine for five, ten minutes
> and I am done.
>
> So I think some practical aspect could be devised that would allow me,
> for those kinds of processes, to have a larger media fill that would
> be more representative but yet not still be overburdensome to the
> industry.
>
> So that is one aspect. I think the area of environment monitoring is
> another one that could use quite a bit of maybe further explanations,
> especially in the area of alert action levels and what do I do in
> response to those, could use with a little bit more because that is
> also a very confusing part in the industry.
>
> So there are a couple of areas where I think more specifics would
> really assist the industry even without becoming too prescriptive but
> just giving guidance on what is the expectation, what is it that FDA
> wants to see when they come in to a facility.
>
> I spend an inordinate amount of time dealing with those kinds of
> topics. They are very significant. One thing I was very happy to see,
> at least in this concept paper, is the emphasis on doing trend
> analysis as part of that investigation and determining whether I need
> to do an extensive investigation of an environmental excursion or
> whether I don\'t have to do very much.
>
> DR. LEE: Excuse me.
>
> MR. MUNSON: Yes?
>
> DR. LEE: Let me focus the discussion a little bit more. I think I
> might want to get my electronic gavel back, if necessary. But I don\'t
> think I need to. First of all, I think we only have about twenty-five
> minutes and there are six panelists here. We would like to hear from
> everybody.
>
> MR. MUNSON: Okay.
>
> DR. LEE: My fault. I did not make things clear. Moreover, we would
> like to hear your thoughts on design, control and contamination at
> this point.
>
> MR. FAMULARE: That\'s right. The way we focussed the afternoon
> discussion is that, at least in this first part of the discussion, we
> will talk about design control and contamination, particularly the
> talk of Berit Reinmuller. And then we will go to sterilization
> options, personnel, environmental monitoring and media fills and then
> have the panel be able to discuss each one of those.
>
> So there was a break from Berit Reinmuller and there was a little
> confusion there. But we would like to at least focus this first part
> of the discussion until Kris Evans comes up on the design, control and
> contamination.
>
> So we have all that media-fill comment and we will get back to answer
> that when we get to that discussion with Brenda Uratani leading that
> off. So if we could get the group to focus on those, starting with the
> design, control and contamination.
>
> DR. LEE: Please.
>
> MS. LOWERY: In terms of design, control and contamination, I think
> that the presentations given so far, in terms of the controls that
> have to exist in the aseptic-processing area in the critical zone are
> very important. Most of these focus, I guess, like we talked about a
> little earlier this morning on personnel being the major source of
> contamination in a clean room.
>
> Once contamination is identified, obviously it is a little easier to
> deal with, but, in looking at the way people interact in an aseptic
> process makes a big difference between a product\'s sterility and
> nonsterility.
>
> So, in looking at the design aspects, I think that it is extremely
> important to look at the positioning of personnel in the critical
> zone, how they interact, to have their interactions be very well and
> clearly defined in standard operating procedures such that everyone
> knows how to intervene in the aseptic process with sterile tools and
> implements, et cetera, so that air flow is not disrupted and there is
> not the potential, then, to deposit particulate, viable and nonviable,
> into the aseptic product.
>
> So that is a big concern is that the training of personnel, et cetera,
> in these areas as it relates to design control is something that may
> need to be a little bit more focused.
>
> In terms of general contamination issues, in the clean room itself, I
> think there are several routes of contamination ingress into the
> aseptic-processing area. Certainly the biggest one is probably
> personnel. The other one is bringing materials and equipment into the
> area that go through an airlock or a pass-through and don\'t go
> through an autoclave or a dry-heat oven.
>
> The potential for contamination there is great and usually I think
> what happens there in that particular scenario is that there is not a
> big focus on surface disinfection of these parts with a sporicidal as
> they ingress into the area. It results in the spread of contamination
> from one part to the surface of another through the operator. So the
> operator is basically a vector of contamination.
>
> So I think that is a focus that needs to be brought up in terms of
> looking at the potential for controlling contamination in a clean
> room.
>
> MR. FAMULARE: Do you have any specific suggestions in that regard
> toward the guidance as it is written, towards the concept paper?
>
> MS. LOWERY: The concept paper could probably be a little bit more
> strengthened in terms of the particular aspect of the controls of
> bringing equipment and materials in through an airlock or through a
> pass-through. I think that has to be a qualified process. I think you
> have to use qualified disinfectants that have been shown to be
> effective against the bioburden that typically might be on these items
> as they are brought in. Then, the process, itself, should be qualified
> so that there is complete assurance that there is no contamination
> being brought in that way.
>
> There are other areas as it relates to personnel, then, in terms of
> gowning and what kinds of requirements maybe the guidance document
> should be strengthened on in terms of looking at gowning and the
> potential for people to bring in contamination which is the other
> viable route.
>
> DR. LEE: Did you have something to add?
>
> MR. MUNSON: Yes. On a design issue, I think a lot of us are focussing
> on the aseptic core. There is a huge part of most factories that is
> outside the aseptic core and, again, this is where the material
> movement and personnel movement\--I think this is one of the
> weaknesses in the guide is this interaction between these areas that
> either support the aseptic core or are in front of it.
>
> These are like putting transition points in between places like
> warehousing and then I start to move materials and personnel into a
> \"manufacturing\" area of the plant, maybe compounding areas, things
> of this\--these are non-sterile areas, but I think it is critical to
> set up, from a design of a facility, transition points where I have to
> do this decontamination or I have to try and retard contamination
> coming in from uncontrolled areas into cleaner areas.
>
> So, the plant should be designed to get cleaner and cleaner as I get
> closer and closer to my aseptic-processing areas. I think this is
> something where the guideline really doesn\'t even get into that part
> of the facility and how that can play because that is all part of the
> \"contamination control\" aspects that should be built into a sterile
> manufacturing facility.
>
> DR. LEE: Thank you.
>
> Don?
>
> DR. BURSTYN: I will try to be brief to leave some time for Mike at the
> end, here. I think that it is very\--I want to make two points. First
> of all, we need to figure out a way to allow a more rapid
> implementation of new technology. It is clear that many of us go back
> to older technology because we are used to it and the agency is used
> to is and it is very safe for us.
>
> We do avoid new technology because none of us really want to be a
> pioneer, the first one out there, and risk the chance of our approvals
> being delayed. Just a second fast point I want to make is that reading
> through the document and hearing some of the talks, it is obvious that
> there are many parameters within a conventional fill room, within an
> isolator, of whatever, that we can monitor.
>
> We can look at air flows at various areas. We can do environmental
> monitoring and such like that and we can collect a lot of data. We
> need to make sure that, just because we can collect data, that should
> not be the reason we are doing it. We need to make sure that the data
> we are collecting absolutely has some meaning to us and that we can
> use that data in order to help us to improve the quality of our
> processes and to ensure that better-quality products are getting to
> the end users, the patients.
>
> So just because we can measure something, we shouldn\'t. We need to go
> back and really think about what we are doing.
>
> I will leave it at that.
>
> DR. LEE: Anne Marie?
>
> MS. DIXON: I want to make a few comments on design. I think part of
> the problem starts when you don\'t lay out a process and then you
> don\'t have the adequate space in order to move items throughout the
> facility. So the first thing that should be done is to analyze the
> process flow and then build the clean room or the controlled
> environments to suit the process.
>
> When you try to shoe-horn it in, it gets to be very, very difficult.
> So that is going to give you a lot of entrances and egress areas for
> personnel movement and for things that go on to the areas. These are
> going to need multiple levels of control. Just adding a locker room
> two buildings over and having people tromp around through the outside
> in order to get over to the aseptic filling room doesn\'t work.
>
> Yet, those are some of the things that people do every day. The same
> is true with bringing things off of trucks and then going through a
> passive airlock or passive pass-through and then assume it gets
> decontaminated.
>
> So, having multiple stages of facilities, multiple egress and ingress
> points I think would be, in addition to the process flow would be very
> beneficial.
>
> But then, when you get into the inside facility, I think we are having
> problems with things like smoke studies and trying to qualify design.
> Smoke studies, certainly, in a passive situation, are much different
> than a dynamic condition which the two speakers earlier have shown us.
> But, not only that, the type of smoke could be a serious issue.
>
> There are many smokes that are used today that are carcinogenic in
> nature and I think it is important for the Agency to understand that,
> that we just don\'t want smoke. We don\'t want a contamination thrown
> in the clean room just because we are trying to prove laminarity or
> unidirectional flow. But we want good science applied and want to
> actually see the movement of equipment, see the movement of people,
> and see the fact that the clean room can sweep items away.
>
> That points back to having good filtration. Filtration is something
> that is very expensive today. Many firms, in their effort in order to
> cut back on costs, and \"think green,\" are talking about reducing the
> velocities in the clean room, turning the clean room off at night and
> then going back to active condition in the next day.
>
> This does seriously detrimental effects on a clean room. People are
> failing to go back to some of the original work that was done back in
> the \'70\'s and the \'80\'s and the \'90\'s by other industries in
> this clean-room field which have proven how you move particles, how
> you control particles, what happens to microbial during shut-down
> times, what happens when you reactivate fans.
>
> So I think this whole science of the system and the design has got to
> be looked at very carefully. Otherwise, all the monitoring and all the
> training is going to be to no avail.
>
> MR. FAMULARE: Again, do you have specific areas where you think the
> guidance needs to be beefed up in this area or changed?
>
> MS. DIXON: I think it might be beneficial for the reader to have some
> references, in not just beefed up in some areas. I think we have got
> to address multiple use of airlocks. We have got to say something
> about using an active versus a passive unit. I think we have to say
> something about HEPA filters and making sure that these HEPA filters
> are tested with the appropriate standards by giving references.
>
> We need to go back and reference some of the original work done by
> some of the aerospace people, some of the NASA people right here at
> Goddard, which have proven what happens to clean rooms when they wind
> up being turned off at night and reactivated during the day. So the
> user can go back and look at this.
>
> I think some enhancements on egress and ingress and some enhancements
> on references would be very helpful.
>
> DR. LEE: Jeanne?
>
> DR. MOLDENHAUER: I concur as far as this ingress/egress. I also
> support Sandy\'s comments about needing more guidance for validation
> of pass-through as this tunnel\'s disinfection and that as well. I am
> also concerned about just some of the things that are put in the
> guidance document; for example drains, and that drains are bad in
> clean rooms.
>
> That is great, except that I have a lot of processes that are very
> moist in nature, compounding, washing componentry. If I don\'t have
> drains, then I have standing water in clean rooms which is not really
> a good thing. So I think we need to go back and look at that. I agree
> that it also needs more references.
>
> DR. LEE: Mike?
>
> DR. KORCZYNSKI: I sent my FDA colleagues five pages of comments on the
> document so I am not going to reiterate those comments. I just wanted
> to play off some of the comments I heard today and maybe indicate some
> areas for inclusion in the concept paper.
>
> One thing, for the sake of maybe providing some information to the
> panel, in some cases, I disagreed slightly with some of the speakers.
>
> DR. LEE: Let us focus on design, control and contamination for now.
>
> DR. KORCZYNSKI: Frankly, this is difficult to do, just given that
> direction in a moment. I would like to be able to just cite a few
> comments that I think are going to be beneficial to us. In this case,
> it was cited that aseptic individuals, perhaps, need better training
> and maybe the industry is derelict in that regard.
>
> Well, I think people, in general, have to remember the industry has
> come a long way in aseptic processing. Along those lines, people
> receive yearly GMP training. People have to be validated in gowning.
> The industry, in many cases, has actual limits of 1 to 2 counts. It is
> getting to a point where basically the total process has basically
> improved.
>
> If there is an area for potential improvement, if we look out in the
> next ten years, I would say that maybe would should consider a
> certified aseptic operator-training program, an aseptic certified
> program, for people who operate in manufacturing areas.
>
> That could be developed by industrial associations in concert with the
> FDA and maybe an oversight could be the university that issues the
> certificate. But I think that that would give us some level of
> standardization among all operators regardless of whether they are
> with a small firm or large firm.
>
> The other issue I found relative to the document, a key one. It is
> just like many of my colleagues said. I found it wanting in terms of
> not saying anything about the action levels relative to media fills.
> To those that are unacquainted, a media fill is a way of replicating
> the process and giving you some feeling that you have validated the
> process.
>
> It is not the total answer but it is a pretty good answer. Of course,
> there has been an arbitration through this through the years. Many
> people classically have been using a 10 percent mathematical approach.
> I think where the industry has improved is that, in my own experience,
> there seems to be a target level of 0 out of 3,000.
>
> As a matter of fact, people have moved that up to wanting to see no
> positives out of units 3,000 to 6,000. Companies feel uncomfortable
> when then get one to three positives out of about 6 to 9,000 units. I
> think everyone feels uncomfortable in an initial validation if you
> have a hiccup in three replicate runs, whether that be one positive or
> three. That is inadequate. You have to go back until chronologically
> or sequentially you have three good runs.
>
> So I think the document needs to address something along those lines.
> The other place where I found it wanting is what about the clinical
> fills. What about operations that are filling small clinical units,
> 500 to 1,000 units, basically? When do you conduct a media fill there?
> I would say that the isodocument on aseptic filling has a section that
> should be considered and reviewed.
>
> Relative to this discussion on limits and levels, I think that that
> can be variable. I am frankly a proponent of limits because, in many
> cases, many companies put their environmental counts in their
> specifications because it becomes part of their work-order procedures
> as well.
>
> Basically, I think that one item I asked for inclusion in the document
> and it will appear stringent on the part of some of my industrial
> colleagues, but I think there should be a management review. When you
> have a number of counts that exceed your limits or levels in the Class
> 100 area, there should be some arbitration as to whether you are going
> to release that product or not, because now we are holding these
> environmental counts to be absolute rather than a trending analysis
> type of an approach.
>
> So that was a suggestion.
>
> I am going to answer one gentleman\'s question about sterility
> testing, the amount of positive units and all that we saw on the
> chart. I would say that, in my opinion, I don\'t think those were all
> reflective of sterility-testing failures because we know the industry
> has improved in sterility testing because many companies are now using
> isolators rather than the testing room to test the product.
>
> As a matter of fact, one failure in the initial test means that
> product is gone.
>
> Just the other comment relative to barrier isolators, maybe what we
> could include in the document. There was discussion of these classical
> technologies versus barrier isolators. However, there is a hybrid and
> that hybrid is the conventional filling line where one may put a
> plexiglass cabinet around it. One may put curtains around that, so it
> is not truly and enclosed isolator but it prevents manual intervention
> during the filling of the product and, surprisingly\--not
> surprisingly; in many cases, those data are excellent in that
> environment.
>
> So that, in summary, is it.
>
> DR. LEE: Okay; very well. What I have heard is the writers of this
> draft concept paper would like to have some specifics which I don\'t
> think is forthcoming, per se. But you hear the sentiment.
>
> MR. ELTERMAN: One of the things I wanted to add to the design and
> controls is one of the things we did wrestle with, what was going to
> be included as part of the scope of the document. To answer some of
> the questions related to the HVAC, we sort of have that on a parallel
> track as a separate guidance document that we see coming out about the
> same time.
>
> We weren\'t in a position to present it here but, again, some of the
> various aspects of that will be covered in a separate guidance
> document.
>
> DR. LEE: The philosophy of this is to be as broad as possible, to
> cover as many bases as possible.
>
> MR. ELTERMAN: When taking a look at scope of this, we realize that
> there are additional things that we needed to have built in which
> would be probably best for a separate guidance document. So there was
> a lot of crossover between what could have been included in the
> aseptic process guidance document and the HVAC document.
>
> So we haven\'t finalized that yet to bring it forward, but there has
> been a lot of cross-talk to try to make sure that the two documents
> harmonize which may address some of the issues that we have heard
> today, at least with respect to the HVAC controls.
>
> MR. MUNSON: I guess, just from a design aspect, though, one of the
> things would have been this harmonization on the ISO designations. I
> guess the biggest push for that is the harmonization effort. One of
> the things that is not in the document is doing a conversion from
> European 209 and ISO because that has got to be one of the most
> confusing things the identify has been wresting with is doing that
> conversion, because the European designations have an inoperation and
> a static mode and it\'s okay, and which one are we referring to.
>
> People mix those up. They are using Class B\'s as being equivalent to
> a Class 100 U.S. But, again, we are mixing those up. So I think the
> document, if you were going to go back and relook at it, would be to
> do the isodesignations throughout the document and then just have a
> really small table in the front that would do the conversions as to
> what that means in the old terms and in the current European system,
> so that everybody would be very, very clear on what you are talking
> about.
>
> But moving the rest of the document into the ISO which is slated to be
> the harmonized classification system.
>
> DR. LEE: Comments?
>
> MR. ELTERMAN: Again, that was one of the discussion points that we had
> as part of the committee, how far did we want to go in looking at ISO.
> Certainly, there are concepts that are compatible with our document.
> We just weren\'t, at this point, ready to look at ISO and sort of
> embrace that. So that is a separate discussion probably yet to come
> but I certainly appreciate your comments on that fact.
>
> MR. MUNSON: I am only talking about the classification scheme. I am
> not saying that you have to endorse the entire document. FDA never
> endorsed 209 in its entirety, but just the classification as to what
> do I call what, I think, is the aspect that I am looking for right
> now. Whether you endorse the entire Part 1, Part 2; yes, you can do
> that at some other point
>
> MR. ELTERMAN: We tried to make reference to it as part of the table
> but, in as much as that has caused some confusion, we will go back and
> look at that.
>
> MS. DIXON: In that you are going to be writing a parallel design
> document, then I have two design questions for you. There are two
> comments that are in\--one is in Section C. It is actually listed as
> Line 170 which, actually, exceeds some of the current standards. I
> think the industry would like a clarification of what you mean by 0.05
> inches water gauge from room to room, because currently most people
> are following what was written in 1987 and in between the critical and
> the noncritical, that\'s true and in between the noncritical and the
> ambient, that is true but most people practice cascade between that.
>
> If we are looking at going to 0.05 inches water gauge from room to
> room, then some facilities are not going to be able to meet that
> criteria even though they been licensed using the cascade. So I think
> that is an area that will need the committee to go back and look at it
> for clarification.
>
> The second point for clarification under design, if I could refer the
> committee over to the next page, Page 6, under Line 240, this is also
> a deviation from what the industry has seen in the replacement of a
> HEPA filter should there be a significant leak.
>
> In general, FDA has embraced the IST document, recommended Practice
> 6.2 in its use of a percentage and a size limitation. PDA has since
> even quoted some of that in some of their documents. So my question,
> again, to the committee is are we moving towards a change? Are we
> raising the bar? Was that your intent or is it just a matter of
> semantics.
>
> MR. FAMULARE: We did discuss these areas quite a bit internally. I
> could look to one of the technical people that worked on it to maybe
> come to the microphone if they want to clarify these points.
>
> DR. LEE: Are you looking for volunteers?
>
> MR. FAMULARE: I think either Rick or Kris.
>
> DR. LEE: While Kris is coming to the microphone, let me give you a
> preview about what is ahead. We have four other topics, sterilization
> options, personnel and environment monitoring and media fills to
> discuss. Is that right?
>
> MR. FRIEDMAN: I am just reading on the spot, just to refresh my memory
> on exactly how it was stated. We used the concept that areas of
> different criticalities should generally\--that is one of the places
> where we used the qualifying word\--generally have a 0.05 positive
> differential pressure relative to areas of lower criticality. But the
> word generally was used there to allow for latitude for firms who want
> to use something like 0.03 or something like that so they don\'t have
> to keep stepping up each from one room to one room to one room.
>
> We do want to see the progressive pressure cascade from the area of
> lowest criticality to the area of the highest criticality as a
> well-accepted facility-control concept. If there is a need for
> clarification in the guidance, we could go back and, as we prepare to
> issue draft guidance, we can, perhaps put the example of the
> aseptic-processing clean room and its adjacent lesser-classified room
> in there as the most prominent example, the way it was in the original
> \'87 guidance.
>
> There are other options available, also, that we could consider. But
> we think they were generally provided for those instances and that is
> why we put the word there.
>
> DR. BURSTYN: I think, in a way, it kind of points out that we have to
> be exceedingly careful and very deliberate when we choose our precise
> wording in this because this is often open to interpretation. Not only
> is this, in effect, going to served as a guidance for industry, often
> these documents actually become manuals for inspectors when they are
> coming into your plant.
>
> MR. FRIEDMAN: When you have the word \"generally,\" the advantage of
> the firm is that they can throw back those words and quote them to FDA
> in a 483 response. That is one of the reasons it is a side effect or
> byproduct of this guidance document, but it is an advantage for firms
> that they can then quote this document and say, \"Well, FDA says
> \'generally\' in their guidance document.\"
>
> Also, we have seen a number of firms that, in areas besides\--and this
> is one of the reasons why we have changed the guidance relative to
> only giving on example in the original \'87 guidance, or we plan to
> change it, because we have seen a number of firms that have had a
> progressive cascade between an area such as the unclassified corridor
> that leads often through an airlock into the aseptic-processing
> facility, the introduction to the aseptic-processing facility.
>
> This is another area where 0.5 inches of water gauge is typically
> used. So this is what we were trying to reflect in this guidance. It
> was supposed to be, instead of giving one narrow example, as in the
> \'87 guidance, we were giving more of a reflection of the current
> status of the pressure cascade used by the industry for contamination
> control.
>
> So, again, there are a number of ways to approach this but I also do
> take your comment on improving the precision of the words.
>
> DR. BURSTYN: I appreciate your response but also please remember we
> would actually prefer not to get a 483 than to have a great response
> to it.
>
> MR. FRIEDMAN: Good point.
>
> DR. LEE: Very well. What I propose to do\--we are going to take a
> break. We are going to take a fifteen-minute break ahead of schedule,
> and then we will come back here at 2:40 and continue from there.
>
> \[Break.\]
>
> DR. LEE: Let me remind everybody about what was the general intent of
> the agenda. There is a concept paper for all of us. I think the
> authors of the paper would like to hear from us whether or not the
> document, as written, is scientifically sound.
>
> I have no idea what the intent of this document is going to be. I
> think it is a guidance of some sort. Also, we just heard earlier there
> would be parallel documents developing.
>
> Before the break, I was just curious to know what roll would the
> committee, on the same side of this table, play. I don\'t want them to
> say that we are not involved and take off. Obviously, we would like
> them to participate, like the committee to participate. I would like
> you to listen carefully from the experts, and then advise our
> colleagues as to which way to go, tell them your preference of a
> specific document or something flexible, and whatever you think would
> be scientifically sound.
>
> That is want I planned to say. Now, the next person on the agenda is
> Kris.
>
> **Sterilization Options**
>
> MR. EVANS: Good afternoon.
>
> \[Slide.\]
>
> I am Kris Evans. I am a field investigator with ORA located in
> Philadelphia. I was also on the committee to redraft this document. It
> is my pleasure this afternoon to talk to you a little bit about
> sterilization options available to the manufacturers of sterile
> products.
>
> \[Slide.\]
>
> The Agency recognizes there are options available. Really, there are
> two principles to, terminal sterilization and aseptic processing.
> However, it is very important to emphasize that, in offering this
> document as a guidance to industry, we did not to intend to imply that
> aseptic processing could be used as a suitable alternative to terminal
> sterilization where feasible.
>
> Indeed, and really especially in light of the Agency\'s initiative to
> science-based risk management, aseptic processing continues to be a
> sterilization option of last resort.
>
> \[Slide.\]
>
> In the concept paper, in the scope section, we have included two
> statements in this regard, the first one basically points out, \"It is
> a well-accepted principle that sterile drugs should be manufactured by
> aseptic processing only when terminal sterilization is not feasible,\"
> and, further on in that paragraph, \"If it is not possible to
> terminally sterilize adjunct processing steps to increase the levels
> of sterilization confidence should be considered.\"
>
> \[Slide.\]
>
> I just want to briefly review some of the science behind our position
> but, before I do that, there are a number of terms in the
> sterilization science arena, and I just want to mention two to help
> facilitate this discussion.
>
> The first one is PNSU. It is the probability an individual unit will
> be non-sterile after the application of a lethal agent. So when we say
> a PNSU of 1 in 10^6^, that means the probability that a unit is
> nonsterile is 1 in a million.
>
> The second term is F~o~ or the sterilization process equivalent time.
> It is the equivalent number of minutes as 121 degrees Celsius
> delivered to a unit by a sterilization process. So the term, an F~o~
> equal to eight minutes is saying that a cycle delivered the equivalent
> microbial lethality of 8 minutes at 121 degrees.
>
> Since cycles are not always run at 121 degrees and there is lethality
> accumulated during heating up and cooling down, this F~o~ term enables
> us to compare different cycles under standardized terms and the
> probability of the non-sterile unit concept allows us, since
> demonstration of sterilization is not an absolute but is talked of in
> terms of probability, we use this term.
>
> Historically, a probability of a nonsterile unit of 1 in a million, or
> greater, has been the threshold for sterility by terminal
> sterilization.
>
> \[Slide.\]
>
> To address the question of is this, indeed, happening in industry, do
> we have instances where firms are aseptically processing product where
> terminal sterilization is feasible, the Agency doesn\'t really have
> information on that. But a recent PDA Technical Report No. 36, which
> surveyed the industry, asked this specific question at your site; \"Is
> aseptic processing used for products that could be terminally
> sterilized?\" They defined the \"could be terminally sterilized\" as
> \"capable of receiving an F~o~ greater than or equal to eight minutes
> in its current configuration.\"
>
> \[Slide.\]
>
> The response to that question showed that approximately one-third of
> the firms, indeed, have products that meet that criteria and, of those
> firms, the side bar to the side shows that 2 to 85 percent of their
> products are affected. So if, indeed, your firms are processing
> aseptically where terminal sterilization is feasible, that is
> happening with 2 to 85 percent of their products.
>
> \[Slide.\]
>
> Again, to address this scientifically, we are talking of sterilization
> in terms of the probability of a nonsterile unit. For terminal
> sterilization, we were able to design and qualify cycles to achieve,
> indeed, a probability of a nonsterile unit of greater than or equal to
> 1 in 10^6^. Those processes generally only have this one critical
> step, at least from a sterility-assurance standpoint, of controlling
> the final or terminal-sterilization cycle.
>
> DR. MOYE: That is one in 10^-6^?
>
> MR. EVANS: Did I say 1 in 10^-6^?
>
> DR. MOYE: No. It is a probability or not? Is it a probability?
>
> MR. EVANS: There are two different ways to look at this. I have tried
> to standardize it and it does get confusing. We speak of the
> probability of the nonsterile unit greater than 1 in a million. So the
> probability that a unit is nonsterile would be 1 million or greater.
> There is a sterility assurance-level concept that goes to the negative
> inverses, but we don\'t want to do that today.
>
> Aseptic processing, on the other hand, it really is scientifically
> impossible to establish or determine or qualify the probability of
> nonsterile unit. So there is a fundamental scientific gap, and we will
> look at that, between the ability to scientifically demonstrate
> sterility.
>
> As we have talked about, the process involves multiple steps that
> factor in to the ability to produce noncontaminated units.
>
> \[Slide.\]
>
> Just quickly, the contamination rate, and I put that in quotes because
> that is a different concept than probability of nonsterile unit, can
> be assessed with media fills. So you can look at the rate of
> contamination within a media fill but that is different from
> qualifying the probability of a nonsterile unit. So it is important
> not to confuse those two concepts.
>
> \[Slide.\]
>
> The PDA also asked another question, and they asked firms to estimate
> the probability of a nonsterile unit for their aseptic processes. What
> I have tried to show graphically here is that, if the red is the
> percentage of firms that can meet or exceed this probability of
> nonsterile unit and the yellow is the percentage of firms that can
> also meet or exceed that PNSU\--it is a little tough to read, but at
> 10^2^, or 1 in 100 PNSU, pretty much both processes will meet or
> exceed that level.
>
> Since terminal-sterilization cycles are qualified to really meet or
> exceed 10^6^, that bar remains relatively constant. But as firms have
> estimated, their ability to meet probability of nonsterile units
> degrades fairly quickly and there is the gap, in essence, between the
> ability to produce sterile products aseptically versus terminally.
>
> This is 10^5^, that is a probability of nonsterile unit of 1 in
> 100,000. 35 percent of the firms estimate they can meet or exceed
> that.
>
> Adjunct processing, as we have proposed, would, in essence, shift all
> of the red bars to the right a little bit and move a higher percentage
> of aseptic-processing firms closer to this 10^6^ zone that we have
> historically defined as the threshold for sterile products.
>
> How far it moves to the right is difficult to assess, but I think,
> intuitively, the concept of adding additional heat to improve the
> percentage of firms reaching the higher levels of assurance is pretty
> intuitive.
>
> \[Slide.\]
>
> Just briefly, this is the slide the Joe had on recalls. It is the same
> one, all in one color. But I want to point out two key points. The
> lack of sterility assurance is the number-one reason for drug recalls
> in the last five years, and nearly all of the drugs recalled due to a
> lack of sterility assurance in the last twenty years were produced via
> aseptic processing.
>
> So I think recalls, albeit a somewhat indirect metric for sterility
> assurance, certainly the science, or looking at it from this
> perspective, shows there is a concern, a gap between aseptic
> processing and terminal sterilization.
>
> \[Slide.\]
>
> We briefly looked at the global scene, what are some of our
> counterparts doing around the world. EMEA, the European agency, has
> put out a decision tree on which sterilization option to take. They
> recommend, if possible, terminal sterilization in F\'s above greater
> or equal to 15 minute and, if that is not possible, a form of adjunct
> processing, F\'s above greater than or equal to 8 minutes and also a
> probability of a nonsterile unit of 1 in a million. If that is not
> possible, the last resort would be aseptic processing.
>
> This is formalized in a decision tree for products subjects subject to
> the regulation.
>
> \[Slide.\]
>
> While we have similar concepts, I just want to point out two notes
> that are in that document. They say basically if a choice is made not
> to utilized terminal sterilization, scientific explanation and
> justification should be provided in the dossier, so they are looking
> for written justification in the application for not pursuing terminal
> sterilization.
>
> The second point is heat lability of the packaging material should not
> be, in itself, the sole criteria for choosing terminal sterilization.
> We haven\'t been that specific in our document. At this point, we
> recognize that this issue will require a kind of a multifaceted
> approach but the document with this subject matter would be remiss if
> we didn\'t really emphasize our point that terminal sterilization is
> the preferred route where feasible.
>
> \[Slide.\]
>
> In conclusion, we just have two questions for the advisory committee
> and the panel of experts; should terminal sterilization be used when
> feasible and should adjunct processing be considered in order to
> increase confidence in aseptically produced products.
>
> DR. LEE: Thank you.
>
> Yes?
>
> DR. BURSTYN: I would like to ask a question first. I was at a meeting
> yesterday where Kathy Zoon, who heads up CBER, made a point that there
> were no recalls within CBER due to concerns about sterility assurance.
> Most of the products have all\--well, the majority of them within
> CBER\--are actually produced by aseptic processing, which, to me,
> implies that most of those 50 numbers are coming out of CDER or
> CDER-regulated products.
>
> Can you comment, or can you speculate on why there might be such a
> difference between CBER- and CDER-regulated products?
>
> MR. EVANS: Let me just clarify. First of all, it is the number of
> recalls, and each recall could involve multiple lots, for a lack of
> sterility assurance. That doesn\'t necessarily mean there was a
> nonsterile product on the market. The recall is initiated just because
> of a lack of a sterility assurance, but not necessarily the finding of
> contaminated product. It could be GMPs.
>
> This is drugs. I am not sure what Dr. Zoon was referring to. I am
> aware of some recalls, and I don\'t know what time period, certainly
> in the CBER industry or arena due to a lack of sterility assurance,
> not necessarily contaminated product on the market but would have
> fallen within these criteria.
>
> MR. FAMULARE: We could go back and look at that data, but I think we
> really need to focus on, in terms of what the concept paper has said
> on the choice of sterilization options and get the respective input on
> that. But it is data that we will certainly look at with Dr. Zoon.
>
> MR. MUNSON: Just to start off, I do agree with the first question\--
>
> DR. MOLDENHAUER: I just had a question, still, on his presentation.
> Since you are giving us all that data about recalls, could you please
> tell me how many of those were confirmed nonsterile products?
>
> MR. EVANS: No; short answer. Rick is raising his hand. The data came
> from the Center for Drugs and we broadly classify it lack of sterility
> assurance.
>
> MR. FRIEDMAN: We have found, through government laboratories such as
> CDC, FDA laboratories, the firms\' own laboratories, competitors\'
> laboratories, cases where nonsterile products were on the market.
> Sometimes, occasionally, it has been in response to infections in a
> couple of cases.
>
> But the numbers are fairly small. In fact, there were three nonsterile
> products found on the market this past year\--given that the sterility
> test has such insensitivity to even to find the needle in the haystack
> is, of course, of concern to us\--that were found to be nonsterile on
> the market.
>
> Other years, there has been one, there has been five, there have been
> ten. Some years, there have been zero that have actually found on the
> market. So nonsterilities actually found in the marketplace are very
> difficult to get the exact number of what actually might be out there.
>
> I also did a check on Monday, and we have 120 complaints over the last
> five years in pharmacies, hospitals, et cetera, on the product\--I am
> trying to remember the name of the defect category, but product
> nonsterility suspected, it is called, something like that,
> microcontamination suspected. We had 120, approximately. I think I
> have the numbers, actually, in my folder, over the last five or six
> years.
>
> So pharmacies seem to be finding the problems with the products more
> frequently than laboratories find them.
>
> DR. LEE: Let\'s focus back on those questions and become available to
> answer any peripheral questions at the end. Anybody would like to
> offer should terminal sterilization be used when feasible?
>
> DR. KORCZYNSKI: I would just like to briefly comment on the first one.
> I think most of us would agree yes. On the second issue, that becomes
> a little more problematic especially related to practical application
> in the industry. What I mean by that is if you do a screening process
> either in formulation and/or in your initial stability studies and the
> product doesn\'t tolerate an F~o~ of 6 to 8, it is not unlikely, but
> it is highly unlikely, it is not going to tolerate a 2 to 3.
>
> If it is not going to tolerate and F~o~ of 6 to 8, there is probably
> going to be some degradation at 2 to 3 F~o~ and companies are not
> willing to take that chance. The other thing is that you might lower
> the possibility of degradation by using a lower temp for a longer
> time, and that has got a reverse effect at times of giving you more
> degradation than a peak high temperature
>
> Then just from the implementation, you are talking maybe
> sterilizing\--you have an aseptic-processing run of 100 to 500,000
> units to aseptically process, then to move that over to a large SVP
> autoclave to sterilize for an F~o~ of 2 really becomes very
> inefficient and really difficult from an operational viewpoint.
>
> All I am saying is, in theory, it is good. But, in practice, it is a
> little difficult to implement and it may not be possible.
>
> DR. MOLDENHAUER: Along that same line, if you happen to use and you
> can handle an F^o^ at 2, then I would have to wonder if you couldn\'t
> handle an F~o~ of 4 and have a 10^-6^ sterility assurance level with a
> combined biological indicator bioburden-based cycle which, for many
> products, you can by changing your temperatures and your parameters.
>
> But I also am concerned about the costs to us as industry in having to
> add heat processing steps and resubmit all those drugs with new
> stability studies and to support that as well.
>
> MS. DIXON: I have a concern from a different angle and that is that,
> many times, terminally sterilized products receive a lot less
> attention. So I am hesitant to say go for terminal sterilization if
> you are just going to throw caution to the wind.
>
> I think we still have to look at validation of processes. We still
> have to look at\--all the safeguards have got to be in place. Just to
> run something through an autoclave or nuke it to death and then sell
> it to the public, I think, is the wrong approach. I think that we owe
> it to the public to make sure that we give them a safe drug but a drug
> that actually meets the component specifications for which it was
> designed.
>
> DR. LEE: So we, once again, come back to science, common sense and the
> public health.
>
> Kris, good job. Please sit down.
>
> MR. EVANS: Thank you.
>
> MR. MUNSON: As I have already said, the terminal sterilization, when
> feasible, I think just makes good sense. The second one is going to
> take more work to define, again, what kind of heat treatment. The
> other thing is, when FDA tried this before, and we tried this in 1991,
> one of the main things that everybody fell into the trap was they
> said, \"Okay, aseptic processing is 10^3^. I give another 10^3^, that
> is 10^6^.\" They are not additive. You cannot add them, but that was
> something that everybody instantly went off and started doing because
> one is a contamination rate and one is a probability and you can\'t
> add them together.
>
> So we have to do this kind of cautiously, and what are we going to
> define as an adjunct. If I won\'t stand heat, do I have to go to
> radiation? If it won\'t do radiation, do I go to pulse light? When do
> I quit all the adjunct processes that possibly are available out
> there.
>
> DR. LEE: Let\'s come back to that later.
>
> MR. MUNSON: It is just something that you would really have to think
> about a little bit on the adjunct.
>
> DR. LEE: Thank you.
>
> MR. EVANS: Just briefly, if I can comment on that, we are not asking
> to do additive sterility assurance but we are kind of appealing to the
> science of it. If firms, by their own admission, are failing to meet
> that same threshold of 10^-6^, or 10^6^ probability, adjunct
> processing of some form will, as I said, shift those bars to the right
> and they will move a higher percentage of firms to a higher degree of
> sterility assurance.
>
> At what cost and what tradeoff, I think that was the question we
> wanted to pose, does the science and the experience that we have seen
> justify the additional work and cost of proposing this.
>
> MR. MUNSON: But to get back to what Mike brought up as the
> practicality of it is you may have to accept not even an F~o~ type
> treatment. You may be looking at, \"If I can heat it up to 80 degrees
> C for a short period of time, which means I might be able to do this
> with microwave tunnels or something like that that makes it also
> somewhat practical from a processing viewpoint, in which case I won\'t
> kill spores but I can take care of the vegetatives which, if we are
> looking at people as being my primary supply of microorganisms in my
> clean room, that would take care of that source of contamination.\"
>
> So you may have to think of it kind of towards that light which would
> allow you to have some practicality and may take care of the majority
> of the organisms that possibly could constitute the contamination.
>
> DR. LEE: Thank you very much.
>
> We will have the next person. I case you haven\'t noticed, Helen
> Winkle is here. Thank you for joining us.
>
> I think we have gotten into the rhythm of the format. This must be
> Robert.
>
> MR. SAUSVILLE: That\'s correct.
>
> DR. LEE: What are you going to talk about; personnel?
>
> MR. SAUSVILLE: I am talking about personnel.
>
> **Personnel**
>
> MR. SAUSVILLE: I am Robert Sausville with the Center for Biologics. It
> is a pleasure to be here today to speak with you and I hope to give
> you a brief overview on the personnel section of our concept paper. We
> were given five minutes each to speak. Kris used his five minutes and
> my five minutes, so it is going to be really brief.
>
> We will do the best we can.
>
> DR. LEE: So what is the short answer?
>
> MR. SAUSVILLE: Yes.
>
> \[Slide.\]
>
> As you have heard during the day today, we employ the risk-based
> approach in the development of this concept paper. This extends to the
> section on personnel.
>
> \[Slide.\]
>
> It is commonly understood, obviously from the discussions we have had
> today, that personnel pose a significant risk to the aseptic filling
> environment which is arguably the most critical control point in the
> manufacture of these products. Organisms can be contributed either
> directly by individuals or they can hitch a ride with the individual
> into this critical environment less controlled areas.
>
> \[Slide.\]
>
> The bottom line is that poor aseptic technique combined with poor
> gowning technique at these critical control points results in reduced
> sterility assurance. Our concept paper suggests procedures to reduce
> these risks. Critical areas should have limited access. Operators
> should be appropriately gowned and practice good sanitization
> procedures both before entry and while they are performing the
> operations.
>
> Personnel should be part of a sound monitoring program, which I will
> get back to in a few minutes and, as has been pointed out, the
> training of personnel is very important. A sound training program
> addresses key issues such as clean-room operating procedures, gowning
> procedures and aseptic technique. Ken, are you listening?
>
> Finally, personnel should be appropriately qualified by completion of
> a successful gowning-qualification procedure and involvement in a
> successful media fill.
>
> \[Slide.\]
>
> Again, as stated before, organisms can be introduced into aseptic
> products and components by direct contact with nonsterile surfaces
> such as operator gloves or entrainment of organisms in the
> laminar-flow air from compromised personnel, either from a couple of
> examples, exposed skin or shedding from the gowns.
>
> In order to avoid these problems, our concept paper describes good
> aseptic techniques including contact of material with sterile
> instruments, do not disturb the laminar air flow with rapid movements,
> talking or obstructions and to move slowly and deliberately.
>
> \[Slide.\]
>
> Getting back to the monitor program, the monitoring of personnel is
> used to qualify individuals for aseptic processing, to reduce the risk
> to the products being filled, provides a snapshot in time of the
> conditions the product is exposed to during aseptic filling operations
> and provides an early warning of potential problems if excursions are
> discovered.
>
> We hope that you agree with our assessment of the risk posed by the
> personnel in these most critical processing steps and look forward to
> your input on this section of the concept paper.
>
> DR. LEE: Any questions?
>
> MR. SAUSVILLE: I do not have any questions other than we hope that you
> agree that personnel pose a great risk in the aseptic-processing area.
>
> DR. LEE: So would should use robots as much as possible.
>
> MR. SAUSVILLE: But we can input if you have anything you would like us
> to add to this section. Hopefully, everybody has read the section
> already.
>
> DR. KORCZYNSKI: Relative to personnel, out in the field, there
> sometimes seems to be a little misunderstanding or dilemma in terms of
> what to do. Tables will cite the action levels for personnel gowned
> and operating in Class 100. Then there will be tables in terms of
> gloves and gowns if they are in a Class 10,000.
>
> But, in most cases, people are sampled after they run the operation in
> a Class 10,000 area and they transition from a 100 through the 10,000
> into a 10,000 gowning room and are then sampled. So some people have
> asked, \"Gee; what data table do I follow, in that these individuals
> had a transition from these areas?\"
>
> I am not looking for an answer, but that is a question that is asked
> frequently.
>
> MR. SAUSVILLE: If it is okay, I will give you an answer, or at least a
> feeling on my part. I think that we would like to see personnel
> monitored as they are exiting the clean room rather than when they are
> in the Class 10,000 area because we want to see the conditions that
> they are in and what they have been exposing the product to.
>
> DR. KORCZYNSKI: What I guess I am describing, in many cases, you will
> have a Class 100 area and it may be a barrier or it may be some type
> of an isolator, basically, and it is place within a Class 10,000 and
> still considered a clean room. But it is that transition.
>
> MR. SAUSVILLE: I understand .
>
> DR. KORCZYNSKI: Maybe we have to give some consideration to either
> describing that or maybe modifying the limits by one value. I don\'t
> know. I haven\'t thought through it.
>
> MR. SAUSVILLE: That makes sense.
>
> DR. LEE: Robert, you did a good job.
>
> DR. KIBBE: I have got a couple of naive questions. Is there any
> contemplation or does anybody have any information about contamination
> potential during a work session with a clean environment?
>
> MS. DIXON: It depends upon the barrier capability of the gown and the
> gowning components. One of the comments I was going to make is that I
> think we should stress in this document that we do have to look at the
> particle-barrier properties and the microbial-area properties of all
> the gowning elements.
>
> In addition to that, I would hope that we would stress that we want to
> see street clothes go away from the gown rooms in order to reduce that
> risk because certainly someone who enters the gown room wearing street
> clothing and then puts on a sterile gown is not going to stay at the
> same level as someone who has had multi-levels of controlled gowning
> before entering some of the pregowning areas.
>
> The other comment is that it also depends upon the person\'s ability
> to gown. Doing this type of gowning technique is extremely difficult
> because one risks the fact of cross-contaminating the exterior of the
> gown as they put it on. So we do have to spend a lot of time looking
> at training and we have to spend a lot of time looking at
> qualifications to make sure that, when we qualify someone for gowning,
> we are actually picking out sites that would not only tell us their
> ability to gown but their ability to handle the gown without cross
> contaminating it.
>
> DR. KIBBE: Has anybody looked at whether or not so many hours into the
> process you are more likely to have an incident which would
> contaminate the field?
>
> MS. DIXON: That has been documented under several technical papers and
> it has been proven, both from a particular standpoint and a microbial
> standpoint. But what we can say in general cases is that once the gown
> becomes moistened, the barrier capability of that gown is lessened
> greatly so that, should a person perspire in the gown, should a person
> get wet during sanitization, that barrier breaks down.
>
> DR. KIBBE: But no one has come up with a guideline that says\--
>
> MS. DIXON: There is data showing that two hours in a face mask with
> talking degrades the face mask. Yes, sir; that is published and that
> has been published.
>
> DR. KIBBE: Should that be in here?
>
> MS. DIXON: It could be. It could be referenced in there. The face
> mask, the use of gloves, was published by the second AIDS Conference
> in Montreal showing a two-hour breakdown on latex gloves, the use of a
> garment of certain barriers, the anti-static barrier being that of the
> two- to three-hour barrier, a herring-bone barrier being only a
> 30-minute barrier, a laminated barrier being one of eight hours. That
> is all published data.
>
> DR. KORCZYNSKI: I believe the concept document doesn\'t address
> temperature control and a suggestion would be made to include 65 to 68
> because if one gowns up in this uniform and stays in there for any
> length of time in an uncontrolled temperature environment, it gets
> terrifically warm.
>
> DR. LEE: I think we are getting into some very technical issues.
>
> DR. KIBBE: I was just wondering has anybody looked at\--I don\'t know
> how to describe it\--at swabbing or sampling from your workers before
> they enter and after to compare whether there is\--do you know what I
> am getting at?
>
> MS. DIXON: The reason I am laughing is that we have seen where the
> clean-room people tend to come out of the clean room actually cleaner
> than they go in, which is rather ironic. But that tends to be the
> caliber of isopropyl alcohol they are using as opposed to the
> clean-room condition.
>
> So, yes; I think you could do that. The problem you have, though, is
> if you plate someone prior going in, you have to be able to remove
> that augur which is going to require some type of sanitization effort
> which is going to break down the barrier on the fabric and thereby
> imposing a high risk.
>
> What you can do is to qualify gowning over a period of time and then
> plate people on exit and get that relative data assuming you set up a
> protocol that doesn\'t allow them to drown themselves with a
> disinfectant prior to exiting.
>
> MS. LOWERY: I also think, looking at monitoring personnel, immediately
> following the gowning process versus monitoring them at the conclusion
> of aseptic processing, we are trying to look at the impact of what has
> gone with their behavior, et cetera, over the aseptic-processing
> duration.
>
> So, really, in all totality, the limits are existing for a firm for
> aseptic gowning qualification should, in fact, be tighter than the
> limits that you allow post-processing because, certainly, if you
> can\'t gown aseptically, there is really no hope for you to go into a
> clean room and present yourself in an aseptic manner.
>
> So that is one recommendation that probably should go into the
> guidance that looks at the ability to have a tighter limit on gowning
> certification than post-processing.
>
> One of the other things, in terms of limits of how long a person can
> stay in a gown in a clean room certainly also has a lot to do with
> their activity levels. If their activity levels are restricted in
> terms of slow movement, et cetera, then possibly that amount of time
> is a little longer than people who are allowed to move quickly and to
> try and do a number of different jobs all in one time frame rather
> than being dedicated to the aseptic process. So that was another
> consideration.
>
> I wanted to say just a couple more things real quickly about some of
> the things that I think should go into the guidance document. One of
> the big things we talked a little bit about, the controls that were
> around the facility prior to even going into the aseptic-processing
> area.
>
> Personnel typically come to work and they change into a
> plant-dedicated uniform and plant-dedicated shoes. Now, if those are
> not truly dedicated, then the person can go outside and be exposed to
> the external environment and to the soil where many types of various
> microorganisms exist and track that basically back into the plant all
> around the entire area.
>
> So, obviously, there has to be control over what the personnel are
> exposed once they have come to the work place and changed into their
> plant-dedicated clothing and shoes. So that is a consideration.
>
> The other thing, if you are going into an aseptic gowning room, it
> would be obviously beneficial to have the least amount of bioburden on
> a person\'s underclothing or clothing that they are going to wear
> underneath the gown, whether that be a plant uniform\--ideally, it
> would be a sterile scrub or some type of way to minimize the personnel
> bioload because, as they go through the gowning process, it is,
> indeed, very difficult to come up with a sterile gown at the
> conclusion of gowning if you are not careful and if you have a high
> bioburden to start, the chances of contamination are a lot higher.
>
> So I think that might be something to look at and, as Anne mentioned,
> gowns as good barriers is certainly something that needs to also be
> examined, whether they are maintained barriers over time. There should
> really be a useful life of gown materials because they are
> reprocessed. They are recleaned. They are resterilized. They are
> gamma-irradiated. There is a useful life and it is not necessarily
> just when the gown has rips or tears in it.
>
> DR. LEE: The next topic is environment monitoring.
>
> MR. SAUSVILLE: Can I say one last thing. Jay, is the temperature and
> humidity control part of the HVAC document?
>
> MR. ELTERMAN: I believe it is, but I would have to defer to Carolyn.
> She is shaking her head yes; it is part of that.
>
> DR. LEE: I think this is teamwork in fine display. Rick?
>
> MR. FRIEDMAN: Just one clarification on this sterility question
> complaint category. There are a number of different categories that
> FDA could use to indicate whether sterility problems exist in our
> complaint system called Drug Quality Reporting System. Sterility
> question complaints are just one of them. I think there is also
> contamination suspected, et cetera.
>
> I checked the numbers and there were 114. Some of them are leaking
> containers, but they are\--when I say pharmacies, they are hospital
> pharmacies using pharmaceutical-industry products or nurses, medical
> professionals that detect that there is a vial that has cloudiness in
> it or a vial that has cracks.
>
> I have looked at the specific complaints and I could give you a few
> examples if we had a little more time. But there are a number of
> different categories. There are 114 in this category over the last six
> years, about twenty a year, where a contamination is suspected on a
> pharmaceutical-industry product for a particular lot. It could have
> one to several units that were suspected, usually one.
>
> So, one day, I will provide more thorough data at a PDA meeting or ISP
> meeting or some other forum.
>
> **Manufacturing Issues Discussion**
>
> **Environment Monitoring**
>
> MR. FRIEDMAN: Atypical environment trends in a sterile facility can be
> detected through the establishment of a sound environmental monitoring
> program.
>
> \[Slide.\]
>
> Because microorganisms are invisible to the human eye, routes of
> contamination are not easily illuminated. Environmental monitoring
> provides critical and meaningful information on the quality of the
> aseptic-processing environment when a given batch is being
> manufactured and also can reveal environmental trends of the
> manufacturing area.
>
> An effective program will identify potential routes of contamination
> allowing for implementation of corrections before a product
> contamination occurs. The environmental-monitoring section of the
> concept paper discusses these basic environmental-monitoring
> principles and the need to have adequate systems for data trending and
> data interpretation.
>
> The are many aspects of an aseptic operation that can directly or
> indirectly affect or disrupt the quality of the environment in which
> the sterile product elements are exposed. Here are some deficiencies
> that can cause or ultimately affect the Class 100 environment; poor
> air-flow patterns, contaminated equipment and material-flow patterns;
> personnel practices such as aseptic method breaches or poor clean-room
> behavior adjacent to the line; room-pressurization problems;
> disinfection-program deficiencies; inadequate procedures to address
> manufacturing anomalies that have occurred or have recurred.
>
> All these have an environmental-monitoring piece. Environmental
> monitoring plays an integral role in each of these scenarios and the
> knowledge of whether execution of procedures or control of such areas
> was successful is important in establishing confidence in the
> sterility of a given batch.
>
> \[Slide.\]
>
> I have discussed this chart earlier. It is used here just to highlight
> the environmental monitoring. The bottom right-hand corner, if you are
> facing it, it just one of the influential facets of a firm\'s
> assessment of their aseptic process.
>
> \[Slide.\]
>
> Risk-based environmental monitoring is about determining where the
> various sources of contamination may be and nipping those burgeoning
> contamination routes in the bud. Risk-based programs include
> meaningful measurement and consider the impact on or hazard to the
> product.
>
> The concept document acknowledges that good scientific judgment comes
> into play when action-level departures occur and it is crucial. Our
> concept paper also notes that an environmental-monitoring program is
> most effective when, rather than using a grid-like approach to
> identifying sample locations throughout the aseptic facility.
>
> It, instead, includes carefully selected sampling locations. These
> locations and the associated frequency of sampling are based upon the
> location\'s relationship to the overall operation being performed.
>
> You see our two quotes from the document. Very quickly, we note that,
> \"Sampling, timing, frequency and location should be carefully
> selected based upon the relationship of the operation,\" and,
> \"Locations posing the most microbiological risk to the product are a
> critical part of the program.\"
>
> The issue that has often been debated is how much data must be
> obtained. One well-accepted risk-assessment concept is that, as more
> and better data is acquired, risk assessment improves. In contrast, a
> lack of data gives one minimal information to address whether a risk
> exists.
>
> However, we acknowledge that environmental monitoring and aseptic
> manufacturing serves to provide a sampling of the environment that is
> adequate to give confidence that environment control existed on a
> given day of manufacture as well as over a longer term.
>
> So this is why the concept paper places most emphasis on locations in
> clean rooms and on equipment that pose the most microbiological risk.
> This is an example of an area that lends itself readily to the cGMP
> initiative to encourage risk-based approaches.
>
> \[Slide.\]
>
> Let\'s take a moment to compare the \'87 Guideline to the 2002 Concept
> Paper on a few key topics. With respect to prescribing numbers in this
> guidance, we are aware that there are regulatory guidelines out there
> and industry documents that do, in fact, prescribe numbers for
> services
>
> FDA has chosen not to do so and, instead, to allow firms to justify
> their surface monitoring limits on their own. We will then inspect
> and, in our other regulatory interactions, look at historical data and
> see if they are well-founded in the data at your facility and also
> considering the location that is being sampled.
>
> With respect to critical surfaces, our original \'87 Guidance says,
> \"Endpoint surfaces which contact sterile drug product or sterilized
> container-closure surfaces should, of course, be sterile.\" The 2002
> Concept Paper more succinctly the states, \"Critical surfaces which
> contact sterile products should be sterile.\"
>
> We say it with no less conviction. We just say it more succinctly.
>
> Establishing action limits; the original guidance stated air
> monitoring action levels without any qualification. The new guidance
> provides that latitude I was speaking of in my earlier presentation
> where different limits can be established \"where justified by the
> nature of the operation.\" So we are not prescribing even air limits.
> We have provided that latitude, a new latitude, in this guidance, but
> they will have to be justified scientifically by data.
>
> Identification; the original guidance says, \"Routine identification
> of the recovered microorganisms should be done.\" Not every isolate
> needs to be identified to genus and species, but you should keep a
> valid database of the identity of organisms including in the ancillary
> areas.
>
> In the 2002 Concept Paper, we say essentially the same thing. We
> stress ID in the aseptic-processing room as the highest product risks
> are generally present in that room. But then we say the ancillary
> areas can have an adequate differentiation and at least frequent IDs
> to maintain the valid database. Again, keeping a valid database was
> implicit in the original guidance also.
>
> \[Slide.\]
>
> Let\'s look at a couple more issues on environmental monitoring. With
> respect to trending, we say that adequate systems should be in place
> to detect emerging or existing problems. By the time a trend is
> detected, that problem may already, perhaps, have product impact.
>
> When a meaningful adverse trend is illuminated by the environmental
> data, the problem needs to be promptly addressed to prevent product
> contamination. This is in accord with all the industry and journal
> publications out there including PDA\'s Environmental Monitoring
> Technical Report No. 13, I believe it is, revised in 2001.
>
> Interpretation; this is the area where scientific judgment becomes
> most prominent in devising the program that is risk-based. No
> statement is included in this guidance. Despite some concerns I have
> had at conferences over the years, FDA has not chosen to put any
> statement in its guidance that a critical zone positive, whether it is
> a surface or it is an airborne count, is a surrogate sterility test.
>
> We don\'t put it there for reasons that are very similar to what Mr.
> Madsen mentioned earlier. However, we do stress how important it is to
> look at the area that certainly would present the greatest point of
> risk in the operation if it became contaminated.
>
> The point is that maintenance of the sterility of those surfaces
> throughout operation is imperative. That is one of the reasons why the
> industry has classically had the 24-hour turnaround, one of the
> reasons for sterilization of equipment. Just so long that you keep
> equipment sterile and run operations per the industry standards over
> the years.
>
> So, instead, our expectation is that that data will be looked at as
> part of the holistic batch decision per 211.192. All data needs to be
> looked at, of course, associated with the batch prior to making a
> release decision for that batch.
>
> So the cGMP expectation is for a holistic batch assessment with
> explanation of significance and impact of environmental or other
> deviations. As Mr. Madsen, again, said, these are deviations. They are
> important deviations and they need to be looked at. They are not
> specifications. They are deviations from action levels or alert
> levels.
>
> \[Slide.\]
>
> So, to summarize our concept paper focuses on potential hazards to the
> product and discusses the need for a sound program. Otherwise, an
> emerging or existing contamination route will likely go undetected. We
> not that there should not be a grid approach but it should be
> risk-based. The nature of the operation determines its criticality.
>
> Strategic collection of meaningful samples based on understanding of
> personnel and material flow through the facility should be elemental
> to the program. Detection of adverse environmental trends should be
> done through development of systems that detect the problem before
> there is a product contamination consequence.
>
> Finally, responsive to identified should include a corrective action
> implemented where appropriate. That is how we say it in the
> environmental-monitoring section.
>
> As you discuss environmental monitoring today, we are particularly
> interested in your input on the following questions; do you agree with
> our stressing that the clean room should be monitored based on an
> understanding of how the process flows and should such points of risk
> be emphasized in the environmental-monitoring program.
>
> What common sampling points in the aseptic processing and support
> clean rooms from your experience are most important to monitor as
> points of risk? Finally, regarding trends, are there certain elements
> of trending systems that provide the best mechanism for prompt
> detection of an existing or emerging problem? Also, what constitutes a
> long-term trend and do you typically see intra-day trends. These are a
> few questions that we are wondering about and we would like to hear
> your feedback.
>
> Thanks a lot.
>
> DR. LEE: Thank you.
>
> Anyone?
>
> MR. MUNSON: As far as to the first one, I do agree on doing it by a
> risk-based approach based on what the process is, how the product
> flows through, what the equipment looks like in the specific area to
> be monitored. So I think that is probably the way to do it.
>
> Typically, for most lines, there is an in-feed. Again, this is where
> there is neither an accumulation table or something like that where I
> have the sterilized product either being put on the line or coming out
> of the tunnel, one or the other. Those are typically an area that is
> done.
>
> The filling environment, obviously, where the solution is added to the
> containers. Stoppering area is kind of another one and, again, this
> may be dependent on equipment design on how far apart those two points
> are on the line.
>
> Then, you have the out-feed and that is more for if it is a
> lyophilized product, you have an out-feed from the actual filling.
> Then, of course, you have got, if it is a lyophilized material, areas
> like in front of the lyo when it is open, being loaded, is another
> area that would have to be monitored.
>
> So those are kind of typical areas that you would see for the majority
> of the lines. Obviously, that may have to get modified again based on
> what your lines actually does look like and how it operates. I think
> one thing that the document doesn\'t do is give a little more guidance
> maybe on when you say the number of samples or the volume, say, like
> for air samples is what you would consider to be an appropriate
> volume, especially for the Class 100 area where I know some of the
> recommendations in the past have been.
>
> In this area, since you are looking for such a very, very low number
> of organisms, if we even take the old NASA Guides back in 1969 of a
> tenth of an organism per cubit foot, that almost requires, then, you
> take a minimum of a 10 cubic-foot sample. It is just putting things in
> there like that.
>
> I think the other area, while it talks about trends, one of the major
> issues here is what is a trend. Even the wording that is used kind
> of\--if I probably polled ten people in here, we would come up with
> ten different definitions of what an adverse trend is.
>
> I think you need to kind of either reduce that size or give a little
> more guidance on what you are looking at being an adverse trend. Is
> that consecutive failures? Is it number of failures within a time
> period? Is it something of that sort because, again, this is kind of
> the stumbling block.
>
> Trending is one thing. Constituting what is an adverse trend, at what
> point do I then have to react to this? It is a critical aspect for
> actually taking this to a more scientific-based process is defining
> trends. So I think this is something that might need further
> discussion, especially if we start going to allowing alerts and
> actions for basically all the areas of a clean room and then having to
> react to those because if I get an organism on one plate, my chances
> of finding out where that came from and what happened, if it is not
> part of a trend, is slim and none just be sheer chance.
>
> So we don\'t want the industry chasing down a lot of ghosts and
> creating a lot of deviations that are going to have no outcome, no
> root cause, nothing to be done. So that is probably the most critical
> aspects as I see it.
>
> DR. BURSTYN: I think the one thing I would like to add to what Terry
> said is that there are some sites that absolutely should not be
> monitored. Certainly, any product contact surfaces or surfaces that
> are actually in contact with sterile materials such as stoppers should
> certainly not be monitored before operations.
>
> In all likelihood, it probably adds no value to monitor those sites
> subsequent to operations.
>
> MS. LOWERY: I would just like to talk a little bit about that comment
> and also about, I guess, looking at environment monitoring from a real
> risk-based perspective. I think we said that the routes of
> contamination into the clean room were likely by personnel bringing it
> in or by the lack of adequate surface disinfection of things coming in
> that don\'t come in through the sterilizers.
>
> If you look at it from that perspective, when personnel, then, are in
> the clean room, I think it is a matter of the spread of contamination
> that may be associated with touch contamination transmitting the
> contamination from one aspect or surface onto another.
>
> So I think one of the things that we need to look at is the aspect of
> touch contamination in a clean room. Where do people pick up
> contamination? Once it is in there, how is it maintained in there if
> you have a good disinfection program.
>
> So if we look at the things that people always touch, door handles and
> telephones and carts and shelves and pens and anything else, those are
> considered the vectors of contamination. Those would be, obviously,
> appropriate to be monitored.
>
> We are looking at it for critical surfaces. One of the main things in
> terms of processing is equipment setup. Equipment setup is a major
> routine intervention that occurs with every batch where the equipment
> is brought in and is set up by one or more operators or a mechanic,
> and there is a lot of manipulation and connection that occurs from
> that perspective and there may or may not be sampling that is
> performed during a critical operation such as set up.
>
> So it would seem that set up would be an appropriate time to gather
> airborne samples\--certainly airborne samples and then, perhaps, the
> setup person after that person has completed operations.
>
> I do think, in terms of critical control-point sampling, you certainly
> would not want to do that kind of sampling, for instance, stopper-bowl
> insides or filling needles. You would certainly not want to do that in
> advance of production.
>
> However, if you are looking at the impact over time of personnel
> intervening in an area, critical control-point sample with it being in
> closest proximity to the product can provide very meaningful
> information.
>
> The last point I wanted to bring up was, again, the surface
> disinfection of items that come in. Those are routinely never on the
> environmental-monitoring program, along with things like particle
> counters and air samplers that are brought in. Those are never usually
> on the routine environmental-monitoring program either. So those, in
> fact, would be items that would be targeted for contamination
> potential.
>
> DR. LEE: Any comments from the committee?
>
> MS. DIXON: I think that we should also consider that particle counting
> serves a very strong purpose in clean rooms today because it is going
> to give us an immediate response is there is a problem where the micro
> data we are going to get several days later.
>
> Looking at setting up routine monitoring, to have particle-counting
> sites in the same area as air microcides in the same general vicinity
> as surface sampling will give you very good picture of what is
> happening throughout the process and it makes it much easier to go
> after identification of potential risk.
>
> In addition to that, I would urge this committee to really strengthen
> the statement on \"atypical\" because we are seeing a lot of
> contamination that is not from clean rooms, it is not from people, and
> should not be there. I would, again, urge you to make sure that you
> strengthen that statement, that people not just look at numbers but
> they look at the type of microorganisms and where they could have come
> from.
>
> MR. FRIEDMAN: If I could just interject for a moment and share
> one\--the opinion of the committee that prepared the Environment
> Monitoring Technical Report No. 13 for PDA, it says, \"One should take
> into consideration the extent of contact or exposure at each element
> that the manufacturing environment has with the product. Sites having
> greater opportunity for contributing bioburden into the product should
> be sampled and monitored. Product-contact sources may include
> compressed gasses, room air, manufacturing tools, critical surfaces,
> storage containers, conveyors, gloved hands, et cetera.\"
>
> Examples of non-product-contact surfaces include walls, floors,
> ceilings, et cetera. One should consider whether critical site
> monitoring would actually increase the probability of product
> contamination. It must be recognized that it may not always be
> practical to select a site at the most critical location because of
> this.\"
>
> So that is a balanced discussion of it, but I think that that
> committee put together a balanced discussion of critical surfaces. I
> thought that might add to the discussion.
>
> DR. MOLDENHAUER: I am a little concerned about the trending
> requirements, not because I don\'t think they are important. I think
> trending is really important. But I am concerned about the companies
> that don\'t have automated systems to do that. There is not a big
> selection of automated systems available and the ones that are
> available have very hefty price tags associated with them.
>
> When you specify about daily, weekly, monthly, quarterly, monitoring
> and fifteen different ways you want to see reports, that is going to
> be extremely difficult for people doing manual systems. If you are
> going to do that, I think you need to have a phase-in period where
> they have an ability to get to a system that has that.
>
> DR. KORCZYNSKI: Just a thought. If one was going to implement the
> risk-assessment system, I think it would be a good idea to have an SOP
> or a letter to file as to the rationale for the selection of those
> sites, getting prepared for a field inspection and the question being
> asked how or why to make that selection.
>
> DR. LEE: Rick, do you have enough input to do the homework tonight?
>
> MR. FRIEDMAN: I have nothing else to add to that. I think there were
> very good points made.
>
> DR. LEE: So I would like to invite Brenda to the podium. Then we have
> some discussion and I would like to open it up and put everything in
> perspective.
>
> **Media Fills**
>
> DR. URATANI: Hi. I am Brenda Uratani, CDER Office of Compliance.
> Certainly, last is not least. I can see that there is great interest
> on the topic of process simulation of media fills.
>
> \[Slide.\]
>
> Will try to cover such an important topic in this five minutes of
> introduction before opening for discussion. In our concept paper, we
> have taken the risk-based approach in assessing the adequacy of
> process simulation of media fill. This approach is scientifically
> based and I believe we are in substantial agreement with that of
> industry as evidenced in many publications.
>
> There are a number of relevant PDA publications on the topic of
> process simulation of media fill. They include the PDA Technical
> Report No. 22 and the PDA Technical Report No. 24 as well as the
> points-to-consider for aseptic processing and a book on the
> microbiology in pharmaceutical manufacturing.
>
> On the different issues concerning media fill or process simulation,
> as I see from those publications, I believe that FDA and industry are
> basically on the same page.
>
> \[Slide.\]
>
> Process simulation is of great value in assessing the capability of
> aseptic processing to produce a sterile drug product. While we agree
> with PDA that although a single media fill is a point-in-time
> analysis, that does not guarantee the sterility of all the future
> batches of product manufacturer on the same line. Successful,
> repeatable performance of the process-simulation studies over time
> provide a high degree of assurance of the final product quality.
>
> In designing a media-fill study, it is important to incorporate the
> same risk factor for contamination that occurs in production line and
> to consider the worst-case condition. I would like to clarify what we
> meant be the worst case.
>
> By worst case, we don\'t mean that you artificially create the
> situation that will cause failure or go to such an extreme. I will
> give you some examples of what we meant by the worst-case conditions.
> They include a maximum number of personnel activities in the
> production run that should be simulated in the media-fill run because
> this number of personnel activities could have an impact on the
> quality of the aseptic environment.
>
> Secondly, when you are using a matrix approach in qualifying a filling
> line, one should consider the type of containers or vials or the line
> speed that has the highest contamination risk.
>
> Thirdly, one should also consider a sufficient number of
> representative interventions to be included in the media-fill run. It
> doesn\'t mean that you have to put all the interventions in one single
> media fill. It can be spread in a number of media fills so that you
> will know what is the contamination risk.
>
> \[Slide.\]
>
> The level of sterility assurance is dependent on the aseptic
> techniques of the operator as well as the environment and process
> control. I think there is a broad agreement that value of this
> mediative study is only as good as is the true representation of the
> actual manufacturing process. So whichever media-fill approach is
> used, the firm should be able to justify the rationale of the
> media-fill design. So let\'s look at some of the critical factors for
> contamination in production that should be considered also in a
> media-fill study.
>
> That includes duration and the size of the run, the line speed and all
> the personnel and manual manipulations.
>
> \[Slide.\]
>
> Although the most accurate simulation will be a full batch size and
> duration, we recognize that it may not be practical or necessary. In
> the concept paper, we stated that the duration of run should be
> sufficient to cover all manipulations that are normally performed in
> the actual processing, and we also said that the number of units
> filled should be sufficient to reliably determine the contamination
> rate.
>
> Our intention is trying not to be prescriptive. Our concept paper did
> not state, in most cases, a minimum number of media-fill vials that
> should be filled. Instead, we would like to allow flexibility and
> latitude. However, we hear the contrary, that you want some kind of
> specification on the number of vials.
>
> So the bottom line is that the batch size of the media fill depends on
> the process, whether it is a large or small production-batch size. The
> line speed also is a factor. The duration of a media-fill run should
> be long enough to challenge the practical stresses of the process on
> the environment, as well as on the operator.
>
> \[Slide.\]
>
> Since it is well recognized that humans pose the greatest risk of
> contamination, let\'s focus, for a moment, on all the human aspects.
> Some of the human activities that can pose a risk to a sterile
> production include the start-up manipulation such as the weight check,
> aseptic assembly of the equipment, aseptic sampling collection during
> filling, aseptic additions, like additions of sterile stoppers or
> sterile ingredients and other routine or non-routine interventions.
>
> \[Slide.\]
>
> Two other aspects of contamination risk that should be considered
> include the maximum number of personnel and the activities that will
> stress the production environment, the aseptic production environment,
> and the effect of shift changes and breaks.
>
> \[Slide.\]
>
> Finally, there has been a lot of discussion regarding the media-fill
> accountability and reconciliation and which are the counted in the
> assessment for the capability of aseptic processing. We came across
> many cases where a firm discards a large number of media-fill units
> arbitrarily. They are not specified in the SOP and they are not
> documented in the media-fill batch records.
>
> We, therefore, feel that there is a need to address this issue and our
> concept paper provides guidance on the criteria where the removal of
> media-fill units are acceptable. Basically, the bottom line is that
> those interventions should simulate what occurs in the commercial
> production run and they should be specified in the SOP in sufficient
> detail with regard to the type of intervention and the number of units
> removed.
>
> The media-fill records should also document all the interventions
> performed and the number of units removed. We also note that many
> firms incubate these intervention units separately, even though they
> are not being counted as part of the media-fill run.
>
> We agree with this approach because it provides the useful information
> for an actual production run to assess the risk of each type of
> intervention and to assess if the number of units removed is
> appropriate, whether they are too few or too many.
>
> Currently, the general acceptance looks like it is one contaminated
> unit in 5,000. The interpretation of the limit to a number of
> allowable positive media-fill units should be carefully considered.
> Even though one or more contaminated units may be statistically
> allowed, it does not mean that it is acceptable for product release to
> contain a low level of contamination.
>
> It is also the general consensus in industry as seen in multiple PDA
> publications that the target for any process-simulation study should
> be zero contaminating units regardless of the size of the media-fill
> run and FDA agreed that target of zero contaminants can be achieved.
>
> Since the assessment of the success of a media-fill run is based
> entirely on numbers and the target is zero positive regardless of run
> size, it is not difficult to see why every unit in the media fill
> would count and should be accounted for. So the removal of any units
> in the media fill should be fully justified.
>
> In addition, FDA recognizes that there may be intermittent incidents
> of low contamination within the allowable limits but if it happens,
> one should look at the trend because it is important for the firm to
> investigate. They could be indicative of persistent problem and need
> to take corrective actions before major contamination occurs.
>
> To summarize, I do believe that our current thinking on this issue is
> very much consistent with that of industry as judged from a number of
> publications. I would like to open for discussion\--especially, I
> would like to ask for your views on this topic and I would like also
> to solicit your opinions on media-fill units removed at set up
> because, at set up time, usually a large number of units are removed
> and this process is very manually intensive and much more complicated
> than most other intervention activities.
>
> We are looking for a scientific justification why they should be
> included or not included as part of the media-fill evaluation.
>
> Thank you.
>
> DR. LEE: Thank you.
>
> Any comments?
>
> MR. MUNSON: Again, just to kind of go through maybe some of the
> shortcomings in the document, one of the things is set up is not
> specifically mentioned as being part of the media-fill process. It is
> not specifically that that is included as part of that, and I know, on
> occasion\--or when it should be done or when you wouldn\'t allow it,
> like in a blow-field seal where it may be advantageous to put a media
> fill on the end of the run in which case I would then have to have a
> separate run that would specifically address the setup of the
> machinery or the equipment as kind of a separate issue.
>
> Duration is one I am a little confused about. What is it we are saying
> there because I don\'t think the data is going to support that these
> rooms actually do get dirtier over time, because we do surface
> sampling and environmental monitoring is done throughout the process.
> I haven\'t seen that many companies that are really\--again, if we
> have got adequate design, we don\'t have really design flaws or
> anything, that would indicate that these rooms are getting
> significantly dirtier over time.
>
> The fatigue factor or operators; most companies I am seeing, operators
> are only in there for maybe two hours and then they go out for a break
> and then come back. So, if a company puts all that down, is that
> adequate justification for not having to do, like, a 30-hour media
> fill, if I don\'t have any indication that the rooms are getting
> dirtier or that people are in there so long that they are getting
> fatigued?
>
> DR. URATANI: The bottom line is the firm should justify how they do
> it. There are many approaches. If your production run is, say, 30
> hours, you don\'t have to fill all the 30 hours. You may be filling
> water in between or\--there many different approaches and PDA has a
> publication that lists the approaches, so the firm can choose
> whichever approach is appropriate for the situation.
>
> As far as operator fatigue, I am not 100 percent sure when you say
> that you have never seen operator fatigue.
>
> MR. MUNSON: It is just that operators tend not to stay in that long.
>
> DR. URATANI: Is that true? Is that true that most aseptic operators in
> the filling room only stay there for a maximum of two hours?
>
> MR. MUNSON: The maximum I have ever seen is four, and that is not that
> often. That is usually when they have had problems and the person
> needs to stay there to correct a problem. But people are not staying
> in these rooms for eight hours at a shot because it is very fatiguing
> due to the demanding nature of the work and everything such that you
> really don\'t want people in much longer than two hours. In many
> cases, they almost have to come out because you have to give them
> breaks.
>
> DR. URATANI: But do think that this is uniform in all industries, that
> all firms only let their aseptic operators stay there for not more
> than four hours?
>
> MR. MUNSON: I think that is pretty much the norm, isn\'t it?.
>
> DR. BURSTYN: I am not sure it is uniform four hours, but, certainly, I
> think all firms really recognize the fact that it is very
> uncomfortable to work in these rooms, being gowned in there. To be
> honest with you, our Environmental Health and Safety personnel don\'t
> allow this to happen because it is very difficult to have somebody
> standing up at a line for this amount of time.
>
> So it really just doesn\'t happen, in my experience.
>
> MR. FAMULARE: I think the focus, then, would be how to best express
> how to conduct a proper media fill in terms of how we expressed it in
> the concept paper. That is what we are really looking for feedback on.
>
> MS. LOWERY: I think one of the things that maybe we could look at
> discussing is the concept of worst-case because, really, worst-case
> can be a lot of different things. It doesn\'t necessarily have to be
> the same set of circumstances for every single media fill.
>
> For example, if you are looking for the impact of operator fatigue,
> maybe one worst-case media fill could be one that you follow on a
> production run and you retain those operators who have just worked all
> day on their shift, and they are fatigues. So maybe they would
> participate in the media fill at that point.
>
> Another type of media fill could be one where you do capture set up
> like Terry\--we were talking about, and maybe that is a different type
> of worst-case, things like\--there are a lot of different scenarios
> that would constitute what is worst-case. So maybe looking at how to
> define what is worst-case, recognizing that it can be different for
> different fills.
>
> MR. FAMULARE: I\'m sorry. I think the term \"worst case\" really has
> to be looked at as we go back and look at the concept paper. Are we
> trying to define a case that is beyond what would ever be the
> operating parameters? I don\'t think that is the intention\--as
> opposed to making sure that we capture most accurately all the various
> manipulations and intricacies that would enter into a media fill and
> be reflective of the firm\'s performance. So, definitely, the
> terminology and so forth, we would appreciate the feedback on that
> terminology.
>
> DR. LEE: Let me go back to Brenda. Brenda, you have specific questions
> for the committee? Right?
>
> DR. URATANI: Yes.
>
> DR. LEE: What are those questions.
>
> DR. URATANI: Those questions are, we have set up criteria where
> media-fill units can be discarded because they are also discarded in a
> production run as part of the intervention. However, in a setup of a
> production run, when it is being simulated in the media fill, that
> process is much more manually intensive.
>
> In a lot of cases, we see firms discard huge numbers of vials. So, is
> there any justification for those set-up units to be discarded or not
> to be counted as part of the media fill, even though they are not
> counted in a production run? That is the question.
>
> MR. MUNSON: But I think you stated that very clearly in that this
> is\--we are to simulate the process that occurs in commercial
> production. So, whether it is manual, it is automated, I have got a
> set procedure for how to manufacture a product. If I clearly define in
> there what is rejected and what isn\'t in that process, then, when I
> do the media fill, I should be executing that same process.
>
> If the batch record doesn\'t say, \"Discard the first 50 vials off the
> line,\" then I really can\'t get rid of those because I haven\'t
> stated in commercial production, I am going to get rid of the first
> 50. So, again, we are back to we want to simulate what occurs in a
> commercial production run as far as what is defined.
>
> Now, I have to define that even as far as if I do X intervention, you
> will clear ten vials on either side of that. That has all got to be
> clearly defined, and you said that. I agree with that concept.
>
> DR. URATANI: But do we have any opinion to the contrary?
>
> MR. MADSEN: Russ Madsen from PDA. We may be looking at two different
> kinds of media fills here. You have the media fills that you do when
> are commissioning a new facility or following a renovation or
> something like that, or you have got a new filling line, and you need
> to know a little bit about what is going on in that filling line.
>
> You might want to run media fills to determine that and, in those
> cases, it might be helpful to incubate the set-up units to try to see
> where you have got a problem or if you have a problem.
>
> I think that is different from media fills on long-running
> conventional aseptic processing lines where you already know that
> information. Those media fills should simulate the actual production
> processes as closely as possible. In those cases, it is probably
> appropriate to discard those set-up units.
>
> So I think you have to look at the two types of media fills and the
> information you are trying to collect from both types.
>
> DR. URATANI: I agree with you. I always think that whether you count
> the intervention units, whether they are set up during the production
> run, is always useful, at least at the beginning, to incubate them so
> that you can gain some information from that and you know that
> whatever is specified in your SOP, that you are discarding ten vials
> or 100 vials. That number of vials is justified.
>
> MR. MUNSON: Again, that is almost like having development runs to
> determine what those specs should be which is a little different than
> saying, \"I am going to use these runs to determine my sterility
> assurance.\"
>
> DR. URATANI: No. That\'s right.
>
> MR. MUNSON: So we are talking different purposes and that should be
> clearly delineated when I set up the protocol for what I am going to
> do and that is where I should define what is this intent of this run,
> what am I trying to prove.
>
> If I am trying to determine if I do this intervention and how many
> units to take out, that is one purpose. I may treat that different. I
> may take the vials off the line in a totally different manner because
> I am trying to look for specific cases here.
>
> So I think most of us are trying to think of this as these are the
> routine media fills that we are using to show that we continue to be
> able to manufacture, in this facility, sterile products. So duration
> is a big factor of having to do these 30, 40, which says, on a
> blow-field-seal machine, I have got to do a three-day media fill,
> which starts to get really, really impractical and also to do these
> switchbacks back and forth between water, media, water, media.
>
> You are entering in a lot of other factors that you wouldn\'t normally
> have during production to do these kind of switch-outs.
>
> DR. URATANI: Are you suggesting, in the concept paper, we want to
> address all kinds of situations, whether it is as high-speed fill,
> whether it is blow-field seal or Form Q seal?
>
> MR. MUNSON: I think this is where the proposal here is not necessarily
> that the duration has to be for a full media fill. I think this is
> where some of the emphasis on the number of units to be done, and it
> basically says, if we put some sort of a minimum and then plus we add
> on to that some factor that takes into account the batch size, the
> maximum batch size, such that you start to get at least enough units
> to make an assessment.
>
> So if I make a 3 or 4 or 500,000-unit batch, that may say, \"Yes; I am
> going to have to fill 50,000, 60,000 units,\" or something, whatever
> comes up. This may be a discussion point for the exact numbers, but
> something that says, \"Okay; you have got to fill 5,000 units minimum.
> If your batches are less than 5,000, you do the maximum batch size.\"
> But it is 5,000 plus 20 percent of the maximum batch size in addition
> to that.
>
> That is how we are going to factor in the huge batches. But it is not
> saying I have to run a three-day media fill. Then, during that course
> of action, I have got interventions. In some cases, you have said
> maximum number of interventions and then, in others, that you have to
> simulate interventions.
>
> So maximum number; is that a maximum number for a three-day run? Or is
> that the maximum number for the number of units that I manufacture.
> Again, we are getting into clarification on that because, as it reads
> right now, it would be, \"I have to do three days\' worth of
> intervention on a 60,000 unit run.\"
>
> DR. LEE: We are going to give Terry a break. Thank you, Terry.
>
> I would like to open it up for a few more comments and then I would
> like to sum up the meeting.
>
> MS. DIXON: I would like to ask the committee to comment on Lines No.
> 639 and 640. I really think that needs clarification because it
> states, in the document, that all personnel who enter the
> aseptic-processing area, including technicians and maintenance
> personnel, should participate in a media fill at least once a year.
>
> I think we need to clarify, does that participation have to occur
> before they are allowed to work in the facility or are we going to let
> them work in the facility and then, whenever the media fill comes
> along, they get to go in and participate. This is causing great
> confusion in industry and it really has to be\--we need a position on
> this because media fills, in some plants, only occur every six months.
>
> In other plants, they occur as a monthly event. So, with the turnover
> in personnel we are seeing in the industry, which is huge, the
> question is, how does a firm interpret this.
>
> DR. LEE: Let me interject here. I think this is an important point.
> There is considerable variability from firm to firm. Therefore, I
> would like the committee to begin to think about what is our advice to
> the OPS as to how to approach this, through a risk-specific document,
> or should we have something which is very broad?
>
> Bear in mind that it has been a number of years since this draft was
> done. Who knows whether we are going to wait another twenty-five years
> for the revision.
>
> So I would like to open this to the experts for their comments and
> then I would like to sum this up and bring everything to a close by
> asking my colleagues around the table about what their advice to the
> OPS is.
>
> DR. HUSSAIN: I think a number of individuals also raised the question
> of PQRI. I am not sure I fully grasp that concept, what aspect are we
> talking about in if I can get somebody\--
>
> DR. LEE: To me, this is the beginning of a dialogue. Let\'s not try to
> accomplish everything today. I think we get a flavor about what this
> document is all about. I think this is a concept paper and I think we
> tend to look at this differently. I can sense that some might prefer
> this to be akin to\--not to that extent, but to the Constitution,
> flexible, subject to interpretation, or something to be a
> cookbook-type.
>
> I think, certainly, our colleagues on the other side had heard the
> comments. I think these comments were based on experience and,
> therefore, I am sure that they will take that into consideration. And
> I heard that there might be Version 1.1, Version 1.2, that sort of
> thing, coming out.
>
> So let\'s hear from the experts on this particular issue.
>
> DR. BURSTYN: I think, to respond to the question, certainly it is
> valid to have an ordered approach where an individual may
> obviously\--who hasn\'t participated in media fill and, as a
> consequence, perhaps, does not have the level of training, will not be
> allowed to perform critical operations over the line and such like
> that but, nonetheless, for auxiliary operations that take place that
> are activities that are completely distal to the operation, that they
> certainly could participate.
>
> Obviously, we kind of view the ability of these folks to do some minor
> activities and observe as part of the training of these personnel. So,
> certainly, there has to be an allowance for that.
>
> DR. LEE: Sandy?
>
> MS. LOWERY: I was just going to say that I think that is a good
> approach to restrict their activities in terms of what they might be
> doing if they have not participated. But what a lot of companies, I
> think, have already done is they are looking at some sort of a
> personnel broth fill as an initial qualification step because it is
> inconceivable that a company could just run a media fill for every
> single person that gets qualified to go into a clean room.
>
> You might be running a lot of media fills in a particular time frame.
> So, in order to not do that, companies have decided, some companies
> have decided, to create a program for operator training that is an
> independent personnel qualification where it is taken off-line. It is
> still with media but it is more of an aseptic technique challenge
> consistent with the types of activities they would be performing
> during routine production.
>
> The other good thing about that is if you put people into a media fill
> that are really not completely trained and there is a failure, then
> you have indicted your entire line because someone is not trained,
> which is not very smart. So it might be that taking it off-line is a
> better option and then just the next time that that person\--the next
> time a media fill occurs, that person participate as well.
>
> But, in the meantime, perhaps maybe they don\'t do as critical of
> operations, but that would be defined by the firm.
>
> DR. LEE: Thank you.
>
> DR. BURSTYN: If I could just make one more just general comment. This
> section on media fill is really directed towards aseptic filling of
> vials. But there are many of us within the industry who are doing
> aseptic manufacture of bulks where we do run media tests for aseptic
> simulations, but I think, in this section, and certainly within the
> rest of the document, that there needs to be some sort of comment, or
> some understanding that aseptic processing is used for operations
> other than filling operations.
>
> DR. LEE: I would like to pose one question which I did not hear
> comment about. Maybe that was because I was falling asleep. One of the
> questions says, \"Does this document encourage innovation in the
> aseptic-manufacturing arena?\" I haven\'t heard any comments on this.
> Does anybody care to address that point?
>
> DR. BURSTYN: I would love to address this one, to be honest with you.
>
> DR. LEE: Bear in mind that we need to adjourn the meeting by 5:00.
>
> DR. BURSTYN: No, no. I will be very brief. A lot of it goes
> toward\--and I have alluded to the fact that we need to make sure that
> we figure out a way to encourage people to use technologies that have
> the potential to add quality to the product. Certainly, isolators are
> one area.
>
> We have heard from a number of folks that the update of isolator
> technology, which ultimately does what everybody is trying to do and
> that is to physically separate the operator from the product. The
> update of that technology in this country has not been very good. A
> lot of it is somewhat because of perceptions through various 483s, or
> meetings, or rumor or whatever that it is actually a very difficult
> technology to validate.
>
> The standards for an isolator are much more rigorous than that for a
> conventional clean room. I think we certainly need to dispel that
> perception and do everything we can do to actually get people to use
> technologies such as isolators, and there are other technologies.
> There are the UVs and such like that.
>
> Again, we have to stimulate people to do this rather than discourage
> them. I would hope that, within this document, or in general through
> other efforts of the Agency, that we make this a very active program.
>
> DR. LEE: Yes?
>
> DR. MOLDENHAUER: I would also like to see\--there are numerous areas
> throughout the document that talk about specific media, specific
> culture methods, specific incubations. At bare minimum, I would like
> to see them put in some exceptions that allow for rapid micro systems
> because this document will be extremely detrimental to the already
> negative perception that people have that FDA will not support rapid
> microbiology.
>
> DR. LEE: Other comments?
>
> DR. KORCZYNSKI: Just reiterating, I think, what the others did. As I
> read through this, I didn\'t see it overly descriptive. I think that
> is good. I think we have to provide companies with the ability to use
> technical alternatives and, if they have the wherewithal and
> confidence to defend their alternative technical methods that they
> might be using.
>
> So I wouldn\'t want to see this document become a road map, or a
> detailed road map.
>
> MS. LOWERY: I agree with that in general, but I think there are
> instances where specifics are needed and they are actually wanted.
> Really, in terms of media fills, duration and yield are certainly one
> aspect of it, acceptance criteria, and, because there is so much
> emphasis put on acceptance criteria, while the target, of course, is
> zero, what would be the acceptable number of units?
>
> This is a big deal and it needs to be defined so that there is some
> sort of guidance that is available for industry.
>
> DR. LEE: Let me now give the committee the benefit of some comment.
>
> DR. KIBBE: I just have a question. Do you have, in here, and I have
> read it a couple of times but that\'s okay, I might have missed it,
> where the guidance covers a positive challenge to the system that you
> are putting in place and what that constitutes?
>
> DR. URATANI: What do you mean by positive challenge?
>
> DR. KIBBE: We are assuming the system will remove microbial
> contaminations. If we never challenge the system with the microbial
> contamination, how do we know it does and is there, in the normal
> workup of putting a system together, a microbial challenge to the
> system that is done\--and it is not in this document; right?
>
> DR. KORCZYNSKI: That\'s right. I think, from a practical application,
> most people don\'t want to go into their aseptic operation and seed it
> with microbes, with spore-formers and all, and see whether that
> influences the media-fill recovery rate.
>
> But there are growth-promotion studies to show, indeed, your media
> supports growth but a very interesting study was used by the PDA and
> this concept was tested at the PDA where they have a training facility
> and they inoculated, purposely inoculated, stoppers, the bowl, parts
> of the line. They used increasing microbial counts. Russ is here. He
> can probably more accurately describe the results.
>
> But it appeared there was sort of a break point at lower levels, 10-1,
> 10-2, 10-3 in terms of log numbers, you didn\'t see much. When you
> started getting into that 10-4, 10-5, 10-6 population, you started.
>
> More recently, that is about the most recent data I have seen in that
> regard.
>
> DR. KIBBE: So if I am a brand-new manufacturer and I am putting a
> brand-new line together, I still wouldn\'t even test it to see if it
> worked with a positive challenge?
>
> MR. MUNSON: You typically don\'t do that. You test the individual
> component of it off-line. In other words, like, for the air-filtration
> systems, you use particles that would\--non viable particles that
> would simulate organisms or challenge it with the smallest sizes.
>
> You do your disinfectants. You can challenge them in the lab, but
> taking known contaminants into a clean room is just not a good concept
> just for fear that you are not going to get them all out or something
> of that sort.
>
> So, basically, you do a lot of this work off-line and then you are
> taking great care when you go back and then use them in your
> facilities just as disinfectant studies are done on each of the
> surface types.
>
> So if you have got formica, stainless steel, a linoleum-type product
> on the floor, you are going to test that disinfectant on each one of
> those surfaces to make sure there are no interactions or
> neutralization of the disinfectants. A lot of these studies are done
> out in a lab outside of the clean room and are just part of the
> start-up process, but you really don\'t take organisms in and
> challenge\--
>
> DR. KIBBE: When you are using a system for making the same product
> over and over again, you are assuming\--maybe I am being a
> little\--you are almost assuming that you start out with a sterile
> product and you are just doing this just to make sure.
>
> MR. MUNSON: This is a capability study. It is saying that the process
> is capable of it. The ongoing\--this is the emphasis on the
> environmental-monitoring program, that it has got to be complete and
> everything, and the trending is looking at how well you are
> maintaining all of these surfaces in your facility.
>
> So it is pulling all of that information back together. I do the
> process simulation and that starts to bring in all the factors of
> people, machinery, air handlers, everything. But I am also doing
> environmental monitoring on a routine basis to make sure that I can
> demonstrate control of these.
>
> So this is where all these other processes that we are doing and all
> this other monitoring, how that plays into that so that I don\'t have
> to do positives. I show that I don\'t have the buildups, that I am not
> having any of the adverse trends that you have heard talked about
> quite a bit
>
> DR. MOLDENHAUER: I think you would also off-line challenge the
> filters, themselves, and that is where you do a positive challenge
> with high levels of bacteria to understand exactly how much retention
> that bacterial filter has, and that is an off-line study. But I think
> that is really where the challenge that you are looking for comes\--
>
> DR. KIBBE: Okay; so you challenge there and you have a process in
> between each run where you know for sure that no matter what load
> showed up on your filters, you have cleaned it out and it doesn\'t
> stay in your system
>
> DR. MOLDENHAUER: That\'s right.
>
> DR. KIBBE: So there is no need to come back in later and rechallenge
> your system even with low levels; right? Is that what you are-
>
> DR. MOLDENHAUER: Yes.
>
> MS. LOWERY: The same thing for sterilization validation. You would do
> the same thing. You would challenge those loading patterns with highly
> resistant, thermally resistant, spores and then prove that they are
> gone.
>
> Really, the only part of this that enters the aseptic process that is
> really not sterile is the person, is the operator and everything they
> bring to the process, itself.
>
> DR. KIBBE: The product has to be considered \"nonsterile\" when it
> starts.
>
> MS. LOWERY: It is, but it is sterile by the time it is delivered to
> the aseptic process. It is presterilized prior to that, unless it is
> terminally sterilized.
>
> DR. LEE: I think you may want to take Art on a field trip.
>
> MS. LOWERY: But the clean room has been challenged and many people
> probably don\'t realize this, that there have been published studies
> on actually challenging clean rooms where the rooms have been seeded
> and then disinfectants have been applied, and the techniques have
> actually proven that, with the proper housekeeping techniques, you can
> do removal of surfaces.
>
> So that challenge data has come out since the work that PDA has done.
> Where there work was really showing the challenge on the components,
> this work was showing the challenge on the ability to clean surfaces
> in a room.
>
> DR. KORCZYNSKI: The fact of the matter is there is very little hard
> data from a scientific viewpoint correlating the contamination in the
> environment to intrusion into the product during filling.
>
> DR. LEE: Art\'s question is very intriguing. We never thought about
> doing this, but I think it is something worthy of thought.
>
> I think there are four questions in the booklet that were posed to us.
> Let me try to answer on behalf of the committee and then the committee
> can tell me I am off-base, if that is the case.
>
> Does the concept paper identify the most relevant topics for guidance
> development in the area of aseptic manufacturing? Based on what I
> heard, it is not perfect but I think it covers most of the territory.
> So I think this needs another iteration.
>
> The B question, and then I am going to let you speak. The second
> question, is that document, the concept paper, grounded on science. I
> think it is. Is it sufficiently detailed to provide industry\--it
> think that is where the problem lies. I think maybe my advice is that
> maybe you need to\--I mean, just my opinion\--as to you may want to
> think about what you want this document to be.
>
> I heard comments about there are places where it is too detailed and
> then there are places where it is not detailed. I think, perhaps, we
> need to think about whether or not you have enough detail. What
> additional considerations\--I think that you may want to consult with
> the experts off-line and I would like to reemphasize that I would like
> to see some kind of a mechanism to encourage innovation, that, after
> all, the document has to be sufficiently flexible.
>
> I think that we need to look forward into the future. I think that
> obviously the document, the guidance, ought to be appropriate for
> today but, since we are all busy, we should not want to be visited too
> often. So I guess the question is how far in advance should you look.
> This is something that is very hard for any aspect of science.
>
> Then, the fourth question is to address each of these areas. I think
> that you get a flavor about what is coming through. So, all in all,
> then, I believe, from my perspective as a layman in this area, that I
> learned a great deal. I think the discomfort is not knowing what this
> document is going to be used for.
>
> But it seems to me that it might be useful, once the guidance takes
> further shape, that the inspectors, the investigators, however they
> are called, will be trained so that they will understand the
> conceptual basis for this guidance and therefore will know how to use
> common sense to respond to the situation in a specific facility.
>
> I do hope that common sense is going to carry us, and with science, we
> should be okay. This is my perspective. I would just to now open this
> up for comments by my colleagues. I think Marv is ready to jump.
>
> DR. MEYER: You really hit on one question that I had, what is the next
> step, what is the time frame, what is going to happen to the concept
> paper next.
>
> MR. FAMULARE: This concept was issued preliminarily in terms of our
> issuing draft guidance, so the idea was to get as much input as we can
> before we put out the draft guidance which will also allow for public
> input. So, by having this session, I think we were fortunate to be
> able to get a good bit of input that could better formulate the paper.
>
> There has been, as recognized by Dr. Lee and brought up by Russ Madsen
> and by PhRMA, the idea of even having additional fora in order to have
> some further technical discussions on those issues. One of them
> suggested was PQRI or a series of meetings, et cetera.
>
> So, taking that into account, the next step would be to issue this
> document as a draft guidance not yet for implementation, then get the
> full public comment and then to issue a final guidance to the
> industry.
>
> The time frame would be dependent upon those forums that we determined
> to get additional technical input. Obviously, we have been working on
> this since 1997 so the impetus is to do this on a quicker pace than we
> have before to get these issues fully aired and be able to go forward
> with the draft and the guidance process.
>
> As you could see from the amount of scientific debate, and so forth,
> it does take a good bit of time but it is a process that we want to
> work on intently over the beginning part of next year.
>
> DR. SHEK: Just maybe a general comment and some kind of a concern, and
> then maybe at least a thought on the pass-forward. We started, I
> think, the meeting in the morning with a big boom. Being part of the
> industry, but seeing some of the matrix in the morning and to some
> aspect not being directly involved with a parenteral product, I would
> be scared as hell to go and buy a vial today and parenteral vials,
> looking at the 10- to 20-fold increase in sterility failures.
>
> That goes out to the public domain. If that is really the case, then
> we have a big problem. But then, during the day, I think we found out
> that we really don\'t know what those numbers mean. Like any other
> matrix, if you don\'t define it, you are very dangerous playing with
> those numbers.
>
> Looking at some of the numbers I have seen, it is one-third of those
> maybe the last three years had to do something which is not directly
> relevant to what we talked about today, whether it is alcohol swabs in
> a kit that were recalled or one issue with one company that something
> happened. I think it is important to exactly know where we stand, what
> are the issues.
>
> Saying that, I want to just make sure that I am not being
> misunderstood. We, as an industry, have to achieve to try to do the
> best. But, on the other thing, I think we shouldn\'t allow the
> public\--I was listening here and there was quite a significant debate
> even of issues like sterility, can we combine terminal-sterilization
> with an aseptic process and ensure that the product at the end\--had
> better assurance that it is sterile.
>
> For example, if I sterilize my components and then I aseptically put
> them together and then, at the end, I am going to expose them to some
> kind of terminal sterilization, do I really add some assurance that it
> more sterile because if something in this process I introduce, some
> microorganism, and I cannot use full terminal sterilization? Did I
> really improve the process.
>
> The reason I am bringing it up is maybe because the model of the PAT,
> and I don\'t know whether PQI\--basically, we had one or two meetings
> in specific areas with specific experts trying to digest and find out
> what will be the best approach, on the long run, might be a faster way
> to go and get a good high-quality document.
>
> DR. LEE: Judy, you are motioning to say something.
>
> DR. BOEHLERT: Why not? I think it is clear from the discussion today
> that the time has come to revise the 1987 document. There is nobody
> that disagrees with that. I also think it was clear from what I heard
> in the discussion that this document that has been put out is a good
> place to start.
>
> It is not the end. There are clearly some technical issues that you
> need further discussion around media fills, on duration, on the number
> of units, around environmental monitoring, around isolator technology,
> a number of issues.
>
> Rick, I think industry appreciates all the latitude words you put in
> there, but those latitude words, as somebody pointed out, need to be
> meaningful to investigators and to industry. They shouldn\'t be put
> there so we have a good defense when we get cited, but they should be
> put there to help the investigator to understand that other approaches
> are viable and are accepted.
>
> We are not looking for good defenses. We are looking for a process
> that we can put in place and defend without getting a 483. So I fully
> support continuing dialogue on these issues. I think putting it out
> for general comment now is a very good thing to do. I think we are at
> that point.
>
> It is not without issues. It is not without things that need to be
> discussed. At least we know what those are, I think, from today\'s
> meeting.
>
> DR. LEE: Anybody else wish to make a comment? Joe, have you heard
> enough?
>
> MR. FAMULARE: I don\'t know if that is the best way to put it, Dr.
> Lee.
>
> DR. LEE: Do you have sufficient guidance?
>
> MR. FAMULARE: That\'s right. I think the meeting today was an
> excellent forum for discussing this document. We made the decision to
> bring the concept paper forward that we have been working on for such
> a long period of time to bring it into this discussion rather than to
> come here and start with a blank piece of paper.
>
> I think that really invigorated the discussion and helped us to cover
> the various points by having this paper out there. We heard some very
> good discussions about the scope of the document in terms of certain
> examples were pointed out, certain things should be added to the
> document.
>
> One example was clean-in-place, steam-in-place. We also heard that
> maybe certain things should not be added to the document. We heard
> some call for using certain terminology that is more modern and
> iso-based. We heard for the call for harmonization wherever possible
> or to, at least, put an interpretation table in to explain our
> terminology against, for example, European terminology.
>
> We had, not necessarily along those lines, but we had mentioned, for
> example, that in the European Union, they look as a first principle to
> see whether the product can withstand terminal sterilization as a
> first principle in going forward and deciding the process.
>
> We, in this guidance document, are just looking at that also as a
> first principle and we are not trying to mandate that that is the way
> every process be set in this guidance document but, again, to at least
> look at the scientific value of that aspect.
>
> We have certainly had a lot of discussion today about the level of
> specificity of the document. If you remember this morning, we
> discussed about meeting the goals of the current agency program
> concerning the GMPs for the 21st Century, having a risk-based
> critical-control-point-based and a program that will encourage
> innovation.
>
> So, while we put in the types of things that we hoped would encourage
> innovation, once we get to those things, such as isolated barriers,
> well then the natural question is, what is your expectation for that
> innovation. Certainly, we have heard a lot of debate around that.
>
> So, again, we want to try to strike the proper balance in the document
> whether we look at various backgrounds or sterilization levels, that
> we are not being so prescriptive to discourage the use of what
> everyone would agree would be more modern technology for higher
> quality but, again, to give some comfort level to the industry as to
> what they are shooting for in putting in place that type of
> technology. As they bring it on new, there is a comfort level that is
> being sought.
>
> There was, as was just discussed, discussion about what additional
> process is needed to further develop the document in terms of this
> committee. There was discussion of PQRI and discussion of any sort of
> series of meetings. We will look at those very intently to fully flesh
> out all the debates and the good discussions that were brought up in
> the various areas that were brought out today.
>
> Again, we basically focussed on five major areas today in looking at
> the document as a whole; design and control, the sterilization
> options, personnel, environmental monitoring and media fill. So we
> will look in those general areas again to see where we could further
> enhance the discussion so that we could put forward the best work
> product.
>
> The main thing to realize is that we will take all this input as we go
> forward in developing what will be our draft guidance for public
> comment. It was very good to have this forum to get the full input of
> academia, industry and the advisory committee and our special guests
> here today in putting forward the document.
>
> The best thing that I would want to acknowledge is to thank my
> colleagues in OPS for allowing this forum now to go forward to discuss
> traditional GMP-type documents. It is, I think, a good segue into what
> we are looking on moving forward in terms of the Subcommittee on
> Manufacturing and the discussion as Ajaz led it off today, and having
> a very technical and controversial issue such as this being discussed
> today I think is a good lead into the whole topic in the advisory
> committee and sets the stage for future successful discussions and a
> wide variety of issues.
>
> With that, I will ask my colleagues from ORA and from CBER if they
> have anything to add. I will go to CBER first.
>
> MR. ELTERMAN: Thank you, Joe. I don\'t have many specifics to add
> although I do appreciate the comments that we received on the document
> today. It is interesting that a lot of discussions parallel the
> discussions that we had internally to get it this far. So we faced a
> lot of those same issues and what you see is sort of the compromise of
> the thought process in terms of the specificity, in terms of the level
> of detail.
>
> The one particular plug I would like to make would be for the last
> appendix. We didn\'t have any discussion on the aseptic processing for
> bulk as it applies to some of the biological products. That was sort
> of an addition that we had to add to the document above and beyond the
> 1987 document because that was something that we felt was needed.
>
> A lot of our products are processed aseptically from start to finish.
> So, to the extent that we could begin to address those issues, we
> thought it was important to include it in an overall document that
> addressed aseptic processing as opposed to having a separate guidance
> document.
>
> So if you have particular comments on that, we would certainly be
> willing to hear them to beef up that section.
>
> MR. ELLSWORTH: I don\'t have very much to add. I join with industry. I
> think it is time that we have a good, solid, science-based guidance
> document on this both for the industry and for the investigators that
> have to often do the inspections.
>
> I guess, from my perspective, I think I have seen a couple of areas
> that were identified. I think it is very helpful\--areas where I think
> there can be more scientific input. I am not sure if I have got it all
> catalogued. I see the area of media fills and environmental controls
> as being two major areas that we probably could use more scientific
> input on.
>
> I would hope that we can find the proper forums to get that input from
> the experts that are in the industry and the consultant side as well
> as the Agency. Maybe PQRI or some other forums might be forums we can
> get stronger scientific input.
>
> We are not going to get all the answers, I think, but maybe if we can
> reach some consensus on the best way to go using that expertise.
>
> DR. HUSSAIN: From an OPS side, I think this was a demonstration of how
> we can work as a team. I think we have tried to achieve that. So I
> think, for the manufacturer subcommittee and, I think, the next steps
> we will taking, the team approach has to work and I am pleased that I
> think it is working.
>
> DR. LEE: To go back to the theme of this meeting, cGMP in the 21st
> Century. The challenge is always to think differently and I think this
> is a good example of making the process transparent and making
> everybody feel the ownership of the product that ultimately will come
> forward.
>
> On that note, should I turn it over to Helen? I think she is going to
> say a few remarks.
>
> **Conclusions and Summary Remarks**
>
> MS. WINKLE: I appreciate the opportunity to have a few closing
> remarks. I will make them quick because I know you all are anxious to
> get out of here. I don\'t want you to pull the plug on me.
>
> DR. LEE: Not yet. I always have to have the meeting end on time.
>
> MS. WINKLE: I just want to go over the last two days and sort of talk
> a little bit about what we accomplished and then I have a few other
> remarks to make as well.
>
> Yesterday\'s meeting was basically devoted to getting reports from the
> two subcommittees, the NCSS and the PAT. I really appreciate the work
> that has gone into especially the NCSS. I appreciate Dr. Doull\'s work
> with that subcommittee and I appreciate the tolerance of this advisory
> committee and that subcommittee as we made some decisions on how best
> to handle pharm-tox issues in the Center.
>
> I think the idea of moving the NCSS to NCTR and developing the
> pharm-tox subcommittee under the auspices of this advisory committee
> will really help us in making scientific decisions in this area in the
> past. I think that the decision is actually a very good one.
>
> As far as the PAT Subcommittee, I think tomorrow\'s meeting will help
> us make some decisions as to where we are going from here. We still
> have a lot of issues we need to discuss. I want to thank Ajaz. He has
> been very, very helpful in working with that subcommittee and helping
> us focus on the variety of issues that are involved in making some
> decisions on where we are going with PAT.
>
> Also, I want to thank Dr. Layloff who served as the chair of that
> subcommittee. Again, I think we are looking at moving this
> subcommittee into the Manufacturing Subcommittee but tomorrow, I
> think, will sort of tell how we are going to handle this in the
> future.
>
> I also, though, want to thank the advisory committee. As I said
> yesterday, I don\'t think we could have moved ahead with PAT either
> from the subcommittee standpoint or from what we are doing internally
> with OPS if we didn\'t have the help of the advisory committee. So I
> really appreciate that.
>
> Just to wrap up on the other things that were discussed yesterday,
> blend uniformity; I think this issue has come to a close. I think that
> the committee has given us enough input now that we can move ahead
> with the recommendations that were provided by PQRI and to go ahead
> and finalize a guidance to put out in draft on the subject of blend
> uniformity.
>
> Again, your comments and recommendations have been invaluable in
> helping us get there. I know you are probably tired of talking about
> it since I think we have brought it up in three different meetings,
> but I really appreciate your input.
>
> The CMC Risk Reduction Project Burden Project, I appreciate the
> comments on this. Yesterday was just mainly an update on where we are
> but I want to tell you I am sensitive to the comments that were made
> here at the committee and also off-line by several of the committee
> members that we really needed to ensure that that initiative was
> coordinated closely with other initiatives including PAT. So we will
> certainly keep that in mind as we move ahead.
>
> I, unfortunately, was trying to get across the Cabin John Bridge this
> morning when Ajaz brought up the topic of the Manufacturing
> Subcommittee. Although I missed the discussion, I do understand that
> it was very helpful in providing input from the advisory committee on
> where we needed to move with this subcommittee and, based on your
> recommendations, we will start putting a membership together and start
> formulating that subcommittee.
>
> I can\'t add much to what Joe and others have said today about the
> aseptic processing. I do appreciate the Office of Compliance coming in
> with their issue. I think it was an excellent discussion and, as Ajaz
> says, a very good way for us to work together as a team, the advisory
> committee, the Office of Compliance and OPS, in laying some of the
> scientific foundations for our decision making.
>
> So I really think today\'s discussion was a success. I really
> appreciate the number of people who have helped discuss this subject.
> I know we had to bring in a lot of experts in this area and, again, I
> really appreciate your time.
>
> I think the discussion today will help all of us in thinking through
> where we need to go from here.
>
> Lastly, I want to just talk a little bit about all of the work that
> went into this meeting. Yesterday, Vince made several comments on his
> observations as far as his time on the advisory committee and what he
> has gotten from it. Part of what he said was that the presentations
> were very, very good. I want to second that. I really appreciate the
> people who have taken their time to present to the advisory committee.
>
> A lot of work goes into these presentations to help the committee
> understand but also to help us at FDA have a better understanding of
> the scientific issues that we need to address.
>
> I, personally, wanted to recognize Ajaz for this. He spends an awful
> lot of time preparing for these meetings and I think that his
> dedication to ensuring that there is a strong science underpinning to
> the regulatory decision process shows through when you hear these
> presentations. So I personally want to thank him for that.
>
> Vince, it has really been a pleasure to work with you. I can\'t tell
> you\--we have really enjoyed it. You said yesterday that you have been
> probably one of the shortest-time chairs ever. You may be a
> short-timer, but, for me, you have been a long-timer. You have
> actually done three of my four advisory committees so, to me, you are
> the chair of the advisory committee.
>
> It is always wonderful to talk to you. You always have very good
> input. I have learned a lot, as I said, yesterday and I think everyone
> on the committee has learned a lot. I especially like the way you keep
> the committee moving. It has been very, very helpful, even though you
> have had to pull the plug several times on the microphone so that we
> will stop talking.
>
> But you have really, really been a big benefit to the committee as we
> have moved ahead. In order to thank you and recognize you for the
> efforts that you have put in, I have a plaque of recognition. You
> probably don\'t want to take this on the plane.
>
> DR. LEE: I don\'t want to take this with me.
>
> MS. WINKLE: So I will just hold it up and we will ship it to you. This
> is recognizing Vince for being the chair of the Pharmaceutical Science
> Advisory Committee for the last three meetings, actually, 2001 and
> 2002. So, Vince, we really appreciate that. Thank you.
>
> \[Applause.\]
>
> DR. LEE: Thank you very much. Actually, this is teamwork. I could not
> have done it, as you know\--everybody on the committee got here not
> because of me. I think they are here because of their own stature. But
> I enjoyed the spirit of teamwork, the committee feelings, and also I
> would like to thank you for the opportunity to serve this committee. I
> think I have learned a great deal. In fact, I learned more and now I
> can go back and teach aseptic fill.
>
> MS. WINKLE: I don\'t know that you will get to escape us completely.
>
> DR. LEE: Anyway, I enjoyed the people around here and you know where I
> am, that I come to this time more often than I am in Los Angeles.
> Truly, I would like to thank all my colleagues on the committee, that
> they are fine people. I think that is a good part of it, the chemistry
> that we discuss openly. I think that we are not afraid to challenge
> the system, like Art tried to propose a new mechanism to\--
>
> MS. WINKLE: That is actually a good lead-in to my next remark.
> Although, Vince, I think you are a really hard act to follow, we
> thought long and hard and decided that Art was a good person to
> follow. So we have asked Dr. Kibbe if he would chair the committee for
> the next two years.
>
> He has willingly agreed. Ajaz and I met with Art a couple of weeks
> ago. We had a long discussion with him over dinner and he made a
> number of useful recommendations for helping us work toward enhancing
> the committee. I think, along with the recommendations, Vince, that
> you have already made, I think we are making a lot of progress with
> this committee. I agree it has been a very collegial group, very easy
> to work with and I appreciate everyone\'s involvement and I look
> forward to working with Art.
>
> I also want to recognize the other people that are leaving the
> committee. Again, it has really been a great opportunity to work with
> some really fine scientists. I think that your contributions to
> science in the Agency has been invaluable and I want to thank all of
> you.
>
> Many of you, as I said yesterday, I hope to see in other capacities,
> maybe working on the subcommittees, on some of those, or in other
> aspects of some of the working groups we may put together. So I do
> look forward to seeing each of you, but I do want to recognize those
> people that are leaving the committee.
>
> This includes Dr. Jusko who will be on our Subcommittee for Clinical
> Pharmacology, Dr. Doull who has also said he will help with the new
> Pharm Tox Subcommittee; Judy Boehlert, who will be working with us on
> the Manufacturing Subcommittee; Dr. Anderson, who has been invaluable
> as the consumer rep. We really appreciate it; last, Mary Berg, who
> isn\'t here today.
>
> So, again, thank you. Thank you for your contributions and thank you
> for the last two days. They go quickly, don\'t they?
>
> DR. LEE: They certainly did, especially with the good discussion.
> Helen, we would have gotten something for you, but you know that we
> could not do so.
>
> MS. WINKLE: Thanks for the thought.
>
> DR. LEE: On that note, a motion for adjournment?
>
> \[Moved and seconded.\]
>
> DR. LEE: The meeting is adjourned. Thank you very much.
>
> \[Whereupon, at 4:50 p.m., the meeting was adjourned.\]
>
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