FDA Workshop

Licensure of Apheresis Blood Products

August 15, 2007

Center for Biologics Evaluation and Research
HHS Office of the Secretary/Office of Public Health and Science
AABB
America's Blood Centers

Lister Hill Auditorium
National Institutes of Health
Bethesda, Maryland

Printable Transcript (PDF, 396 KB)
Note: Documents in PDF format require the Adobe Acrobat Reader®. If you experience problems with PDF documents, please download the latest version of the Reader®.

Table of Contents

Welcoming Remarks - Jesse Goodman
The Regulatory Paradigm and Managed Review - Alan Williams
FDA Review of Apheresis Submissions - Judy Ciaraldi
Top Ten Pitfalls with Submissions - Rosia Nesbitt
Preparing Apheresis License Submission - Stephen Kassapian
Blood Systems' Licensure of 5 and 7-Day Platelets - Kathleen Hopping
FDA Guidance on Collection of Platelets by Automated Methods - Lore Fields
Revisions to the Requirements Applicable to Blood, Blood Components, and Source Plasma - Elizabeth Callaghan
Impact of Very Frequent Plateletpheresis on Donor Platelet Counts - Louis Katz
FDA Regulations and Recommendations for Failure Investigations - Hoi-May Wong
Experiences with a Failure Investigation Program for Apheresis Blood Products - Faye Kugele
Device Manufacturer's Forum
Merilyn Wiler, Gambro BCT
Sharyn Orton, Fenwal
Sue Finneran, Haemonetics
Frequently Asked Questions and Answers

P R O C E E D I N G S

MS. FIELDS: Good morning. My name is Lore Fields, and I want to welcome everybody to the Licensure of Apheresis Blood Products Workshop.

I need to start with a few housekeeping issues.

[Administrative announcements]

We are going to have welcoming remarks this morning by Dr. Goodman. Dr. Goodman is the director of the Center for Biologics Evaluation and Research.

Agenda Item: Welcoming Remarks

DR. GOODMAN: I will try to be very brief, because I know you have a lot of technical material to cover here today, and I think that's the main reason for being here.

On this slide we always kind of show the vision. I mostly want to take the opportunity, in showing this, to thank you folks in the blood community who maintain quality and work with us and deliver this blood system to the American people. We usually are only interacting when there are problems. But I think you can feel pretty proud about the accomplishments and the way we have generally worked together well in achieving your part of these goals: a healthy public and a blood supply that contributes to their health, and where we have avoided or prevented a number of threats or mishaps from occurring.

In addition, you really have worked with us, I think, to improve what we do and improve the industry and the technologies. I think this workshop is in that spirit. I know it's primarily to explain what we do and how you can comply with various guidances and regulations, but I think we also always want to hear from you and understand ways we can achieve the same ends that might be better. So we are very open to that. That helps keep us strong, of course.

Again, this workshop is focused on the processes and procedures in pheresis. I don't have to go through this for you. I do realize, and have heard from the people in OBRR, that identifying the need and agenda for this meeting and some of the questions -- and I also note that several people from the industry are contributing case studies, which is very important to us. There are probably other people involved, but I know at least these folks are involved: HHS, the ABB, America's Blood Centers, and the staff from CBER, who have taken the effort to work with you and put this together.

I know there is a workshop planning committee. The people are recognized here.

Again, I thank all of you on the outside for working with us. That's the way we can succeed, and not just succeed, but do better.

I think that's all I have to say. I am actually very privileged to be able to stay and listen to one or two talks and educate myself some about what you are doing.

So thank you very much.

MS. FIELDS: Thank you, Dr. Goodman.

Our next speaker today is going to be Dr. Williams. Dr. Williams is going to speak on the regulatory paradigm and the managed-review process.

Dr. Williams is the associate director for regulatory affairs in the Office of Blood Research and Review at CBER. In his position, he also serves as the ombudsman, as well as the principal manager responsible for oversight of quality assurance in the department.

Dr. Williams joined the FDA in 2001 as the director of the Division of Blood Applications, where he managed the processing of all regulatory applications reviewed by OBRR, as well as the scientific review of the blood and plasma establishment license applications and supplements and device applications.

Prior to joining FDA, Dr. Williams enjoyed a highly successful 18-year career with the American Red Cross as a senior research scientist.

Return to Table of Contents

Agenda Item: The Regulatory Paradigm and Managed Review

DR. WILLIAMS: Thank you very much, Lore. Good morning.

In addition to those folks that Jesse mentioned as helping to organize the workshop -- and it was a great effort, putting this together, and there was a lot of cooperation between our steering committee and our own internal staff -- I would also like to thank our administrative support staff, who work behind the scenes to make these things run smoothly virtually all the time. So a big thanks to everyone who helped put this together.

The goal of the workshop really is to educate those of you in the audience -- and thank you all for coming -- about what constitutes a successful license application or license supplement allowing you to make licensed apheresis products. Just in very broad outline, we will talk a little bit about the authorities which underlie FDA's licensure process; a little bit about the content and the expectations that FDA has for submissions, as well as the hallmarks of a successful submission; a little bit about failure investigations, because that is very much an important part of the manufacturing process; and a chance to meet and interact a little bit with your consumer safety officers and with some of the device manufacturing folks. This interaction, particularly with our CSOs, is critical if you have questions. They are always happy to receive your calls.

This is really a very important topic, not only for you, but for the agency as well.

This is a slide particular to platelets, pheresis. It just shows some of the growth in not only the overall use of platelets therapeutically since 1989, but the proportion of platelets which have been derived from single-donor or apheresis procedures. In 1989, the total number of platelets administered was about 7.3 million, and about 2.1 million, or 29 percent of those, were apheresis.

I will mention that the data through the years has derived from the National Blood Collection and Utilization Surveys. These were first done by Wallace and Serjiner [phonetic], going back to the early 1980s, then assumed by Marian Sullivan in the National Blood Data Resource Center, and most recently, under DHHS support, the program is managed by the AABB. So it has provided us a very important consistent tracking of our collection and use patterns for various components.

Moving from 1989 through the years up to 2004, you can see that platelets, pheresis became about half of the nation's blood supply around 1994. Now, with a total platelet administration of better than 13 million doses per year, about 9 million-plus, or close to 69 percent of that, is apheresis platelets. So a real growth in the production of this product.

Although the data aren't quite as concise with respect to the collection of red cells and double red cells, I am aware that in at least one major blood collection community, apheresis red cells account for about 30 percent of the red cell collections. This is anticipated to grow immensely in the coming years, particularly as this becomes associated with additional plasma collections.

This is also critical from our standpoint, because we receive a lot of license supplements for review. This simply reflects the incoming applications in this year, 2007, in our Blood and Plasma Branch which are licensed supplements. Typically, we receive about 800 supplements per year in this branch related to blood and plasma establishment licenses. This year we had 314 prior approval supplements, and 14 percent were related to apheresis procedures; CBE-30s -- and I will explain these terms in a moment, if you are not familiar with them -- 120 submissions, about 44 percent of our overall workload; and overall, about 20 percent of our overall workload is represented in apheresis-related applications.

So the smoother we can make this process, the better it is for those of you who intend to manufacture these components and the better it is for us, because it gives us a better application review, less back-and-forth trying to work out problems, and overall just makes it a more efficient and more successful process.

I am going to say a few words about some of the licensure authorities.

For those of you who may not be familiar with our structure, the Office of Blood Research and Review is one of the offices in CBER. We have three divisions. The Division of Blood Application is the home of our Blood and Plasma Branch. This is the area where these applications related to SOPs for blood and plasma establishments are reviewed.

We also have a Device Review Branch within the Division of Blood Applications. But that actually is almost exclusively focused on blood establishment computer software and in vitro diagnostics for immunohematology reagents. The devices related to apheresis are reviewed by our Division of Hematology.

In the first part of the talk, I am going to discuss some of the authorities for licensing blood products; some of the regulations related to licensing; some characteristics of the license process itself and its significance; a very important area, changes to an approved application, how to modify your SOPs once you are actually licensed for a procedure; and alternative procedures.

I wanted to say just a few words about some of the nomenclature. We have found over time in discussing with some of you that some of the distinctions aren't necessarily clear.

The regulatory authorities: The highest level of authority is what is known as a statute, sometimes called an act. These are laws passed by Congress. They can't be violated by you or, in fact, by us, as FDA. This would be the Food, Drug, and Cosmetic Act, the Public Health Service Act, the user fee acts for medical devices and prescription drugs. Some of the areas like safety, purity, and potency of a biologic or a drug are defined in the statute. So we actually don't have the authority to say, "Yes, we recognize that this glitch happened in the manufacturing process, but that's okay; you can go ahead and use it." If it's something that affects the safety, purity, and potency, we just don't have the authority to make that determination.

Then there are the regulations, also known as rules. These are generally promulgated by an agency as rules that carry the force of law. They tend to be more specific than the statutes. There is some provision for flexibility in the regulations and how one needs to carry out one's procedures in response to a regulation. For instance, within the regs themselves, we have a 640.120 regulation, which allows for one-time exceptions and alternative procedures to existing regs.

There are guidance documents, which are the next lower level. These are current thinking of FDA on a particular subject and may be how FDA interprets the carrying out of a regulation, or it might be recommendations related to other areas reflecting the manufacturing process. You are all familiar with guidance documents. It's the most common way that FDA transmits its current thinking.

Then we have our own standard operating procedures. CBER has operating procedures, as do the individual offices.

All of these materials can be found on the CBER Web site. If you look under "Manufacturers," you will see a very organized listing of all of these. So if you want to know what happens to a BLA or a BLS, license supplement, when it's received, you can go there and find administrative processing of BLA. It's there; it's an SOP. It is a very important resource to be aware of.

Specific to some of the statutes, the Public Health Service Act, specifically 351(a), indicates that a license is required for shipment in interstate commerce. This is a key requirement. You don't need a license to produce and distribute within a state, but as soon as you ship interstate, the federal statutes kick in and require a license.

In addition, licenses are required for shipment into or out of the United States.

The Food, Drug, and Cosmetic Act requires registration of drug and device manufacturers, and prohibits the adulteration and misbranding of drugs and biologics.

Within the regulations, the relevant regulations are found in Title 21, Parts 600 and 601. These two reflect the general licensing requirements. Again, under Title 21-606 and Part 211, generally known as the drug regulations -- the 200s -- these cover good manufacturing practice. 610 covers labeling, labeling being everything associated with a product and the information that accompanies that product -- the product insert, as well as the actual label attached to the product itself. Then there are additional standards covered in 630 and 660.

I am not going to read all of this text. This is some of the text out of the regulation. Basically, what this does is to define the elements that are necessary for an application for a license. These include the format of the license application; the data to show safety, purity, and potency of the product; a description of the manufacturing methods; studies to demonstrate stability of the product. In some cases, a sample of the product is required, and in some cases there is a waiver of that sample submission. It provides for submission of the results of lab testing, labeling, and addresses of all of the manufacturing sites.

With respect to licensure, we look for a description of the establishment, including the facilities, the responsible personnel within the facilities who are key to the manufacturing process. Each facility agrees to open up its site for inspection to ensure that the firm is compliant with all regulations and FDA guidances.

The significance of license is such that it signifies FDA's approval of a product under the existing regulations. The license number must appear on all approved products. This, of course, permits interstate shipment of the product.

One thing of note is that while most biological products carry their own individual licenses, blood products are a little bit different. This is an evolution from an old ELA/PLA system, where there was a separate license procedure for an establishment and for a product. Because many of these establishment licenses went way back for the blood establishments, this was converted into what is known as a multiple-product BLA for each establishment. So while the BLA doesn't reflect an establishment license per se, what it reflects is a multiple-product license. Changes in SOPs or a desire to manufacture a new product are accomplished through supplements to an existing BLA license. So it's a little different paradigm than either the old one or the one that is in place for most other biological products.

As part of the application process, we do require a separate application -- in most cases, a supplement -- for each product, a separate application for each operating location, for each manufacturing method. These need to contain a description of the manufacturing methods, an example of the labeling, the products to be manufactured, and the safety and efficacy data if this is a new product.

I mentioned that changes to an approved application are an important element here. This is provided under the regulations, 21 CFR 601.12. This regulation requires a manufacturer to inform FDA about each change in a product, in the production process, in the quality controls, equipment, facilities, responsible personnel, or labeling that is changed in an approved license application or their facility.

The level at which a change in an application is reported to FDA falls into four different categories. These are classified by not only the extent of the manufacturing change, but the level of risk to the product to compromise safety, purity, or potency. For instance, something with a potentially higher risk to affect product safety, purity, potency we would require to come in as a prior-approval supplement, commonly known as a PAS.

Another category is a change being effective in 30 days, a CBE-30. A third one is a CBE and a fourth is an annual report.

There will be more details on this in the next couple of slides.

A prior-approval supplement is changes which require supplement submission and approval prior to distribution of the product that is made using the proposed change. These are generally major changes. This supplement is submitted for any change in the product, in the production process, in the quality controls, equipment, facilities, or responsible personnel, with a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product, as that relates to the safety or effectiveness of the product.

For a change under a PAS category, manufacturers must submit a supplement to their approved license application, including the following:

A detailed description of the proposed change.
The products that will be involved with the change.
The manufacturing sites or areas affected.
A description of the methods used and studies performed to evaluate the effect of the change on the product safety or effectiveness.
The data from those studies.
Relevant validation protocols and data.
Appropriate labeling.
The relevant SOPs or a list referencing previously approved SOPs for that manufacturing site.

Included on this slide are some examples which FDA would consider to be major changes, for which prior approval of a supplement must be made before the product is distributed. This would include:

Implementation of a new manufacturing process, including but not necessarily limited to addition or revision of SOPs, if the change is less restrictive than a previously approved SOP or not addressed in published FDA guidance documents. It's less restrictive.
Changing from manufacturing a sole product by automated apheresis to manufacturing additional products as byproducts of the apheresis procedure, or the request to manufacture additional products.
We will have a lot of discussion about comparability protocols related to apheresis products. The initial request for approval of the comparability protocol comes in as a prior-approval supplement.

Equipment changes also require a PAS:

A conversion from manual to automated collection of components, including platelets, plasma, both fresh-frozen and source plasma, red blood cells, and source leukocytes.
Also included are changes or upgrades in automated apheresis equipment that affect the purity, potency, or quality of the products. These include but aren't limited to increase in product yield, change in storage conditions, change in anticoagulants, leukocyte reduction, and collection of an additional or a different product.
Also a change in manufacturing of automated apheresis equipment used in the collection of red cells or platelets.

The next category is CBE-30. CBE-30 is changes being effected within 30 days. At the FDA side, what this means is that we have 30 days to look at the submission and determine if that level of reporting category is appropriate. If we determine that it is not an appropriate category, we will contact you and ask that the category of the submission be changed.

That said, we have six months to review that application for content. The implication of that is, if a manufacturer makes a manufacturing change before the final review is completed, it's kind of at the manufacturer's risk, that they have submitted adequate data and validation to support that change. So that is one important implication of going ahead and manufacturing a product under a CBE-30.

Under a CBE-30, 601.12(c), changes requiring supplement submission at least 30 days prior to distribution of the product made using the change -- this is generally for any change in the product, production process, quality controls, equipment, facilities, or personnel, with a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product.

I went through the content requirements for a PAS. These are identical for a CBE-30.

Here are some examples of CBE-30 submissions in which we would like to see 30 days before the change occurs. These are generally manufacturing or procedural changes. Examples would be:

Addition of the collection of plasma as a byproduct to an approved plateletpheresis program, provided the applicant is otherwise approved to manufacture the plasma product.
Request for an alternative procedure under 640.120 for which published guidance is available and implementation conforms with the guidance.
Implementation of recommendations described in FDA guidance documents, if followed without modifications and directed to be reported in this manner by the guidance document.

In most cases, an area that a guidance document discusses will have a section in the guidance document referring to what reporting category is appropriate for changes in response to that guidance.

The third category is changes to an approved application, commonly known as a CBE. This is simply a notice to FDA that a manufacturing change is being done. You have the option to implement this change immediately, before hearing back from the FDA. But by the same token, we do have six months to approve this application. Again, it is, to a certain extent, your own responsibility that this change is accompanied by adequate validation and supporting SOPs.

So in certain circumstances, FDA may determine that, based on experience with a particular type of change, the product using the change may be distributed immediately upon receipt of the supplement by FDA. Often these are circumstances which have substantial similarity to a type of change regularly involving a CBE supplement or a situation in which the applicant presents evidence that the proposed change has been validated according to a protocol that has already been approved.

It's important that you retain a record of the date that we received your CBE submission, in case ensuing discussion occurs with the agency as far as the date on which you went ahead and implemented that change.

Here are some examples of a supplement appropriate for a CBE category. These include:

Implementation of another manufacturer's previously approved SOP, with written permission from the manufacturer.
Implementation of recommendations described in final FDA guidance documents, if followed without any modifications and if directed within the guidance document to be reported as a CBE.

The final category is the annual report. This is the lowest risk-related level of supplement. This involves changes in the product, process, quality controls, equipment, facilities, or responsible personnel with a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product.

It's important that manufacturers document any changes to a product, process, quality controls, equipment, or facilities. The annual report must include a list of all licensed products involved, a full description of the manufacturing and controls changes, which include the manufacturing site or the areas involved, the date each change was made, and a cross-reference to your relevant validation protocols or your previously approved SOP.

Examples here would be, under manufacturing/procedural changes relevant for an annual report:

Revision of an SOP for the categories if the change is more restrictive than previously approved or not described in published guidance documents.
A change in the quality-control method if the procedure is consistent with the manufacturer's directions.

Under equipment changes:

Changes or upgrades by the device manufacturer of automated apheresis equipment that does not affect the purity, potency, or quality of the product, if the facility is already approved for the original procedure.
Finally, use of a sterile connecting device to manipulate a product in a sterile manner, if used according to the SCD manufacturer's instructions and use of the device is consistent with that insert.

All of this is spelled out -- 601.12 is a broader category for biologics, but actually blood components have their own guidance related to this. It's a July 2001 guidance, entitled "Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture." That, of course, is on the Web.

In all instances, if you have any questions, if there is something you don't understand and you are wondering what level of submission to put in, it's always a good idea to contact your consumer safety officer. Each manufacturing facility will generally interact mostly with a primary CSO. That should be your point of contact. You should make sure that you go up and say hello to your CSO. If you don't know who it is, just ask around a little bit. Each CSO is assigned a manufacturer whom they work with and oversee, and who serve as a primary facilitator of the license supplement that is submitted to us.

A little bit about alternative procedures. This is defined in 640.120 in the regulations. This is a provision that the director of CBER may approve an exception or alternative to any requirement in Subchapter F of Chapter I of Title 21, regarding blood, blood components, or blood products. This is kind of a special consideration for blood components. Some of it is related to preserving adequacy of supply, particularly under stressed or emergency conditions.

Normally, such requests for exceptions or alternative procedures should be submitted in writing. I will note, however, that there is a process for a verbal request and approval of alternative procedures, commonly known as variances, in the regulations. You should follow 601.12 of the guidance in terms of the category requested. Again, this can be accomplished through the consumer safety officer.

There is a list of previously approved alternative procedures on the FDA Web site. Judy Ciaraldi very diligently maintains this site on a regular basis.

One word of caution about this. While, generally, the titles for the approved variances are listed on the Web site, often the conditions that resulted in the approval or disapproval of that alternate-procedure exception is not given in detail. So don't assume that all situations are similar.

But this is provided as a reference, so that you can see the types of variances that have been approved.

One of the most common requests for variances that has been received in the past is, "Oh, my gosh, we left 100 red blood cell units out on the bench overnight, but the air conditioning was on. Is it okay to go ahead and use this product?" That raises a difficult situation for us, not the least of which is that we have very little information to go on in terms of whether the safety, purity, or potency of that product was compromised. We don't actually have the authority to say, "Go ahead and use that product," if that is not really shown to be safe, pure, and potent through rather compelling data.

We do look very hard at these variances, particularly with respect to he status of alternate supplies, but in many cases we just don't have the ability to say that a product is safe, pure, and potent, in the absence of data to support that determination. So that is an important consideration when requesting variances, particularly after the fact.

I close with just a few words about the managed-review process. When you submit a license application or supplement to us, that starts a chain of events, which is going to be described in more detail by Judy and others in the next few talks. We, of course, have a responsibility to you, as one of our major stakeholders, to help you bring products into the medical community that will help improve public health. So we need to make sure that we are under a managed process to try to get that determination made and help bring you to a successfully approved application as soon as possible.

We work under a system known as managed review. I am going to tell you a little bit about the program and how it applies to blood establishments.

You have heard about the user-fee programs. The two programs currently in place under statute are the Prescription Drug User Fee Act and the Medical Device User Fee Modernization Act. Both of these, you may have seen from news reports, are currently undergoing final deliberations in Congress, now delayed until the end of the summer recess. These are major programs that establish timelines for review processes for the products covered by the user-fee programs.

Blood and blood components are not covered by a user-fee program, but we do use managed review for the applications that you submit to us. What we do is voluntarily follow the PDUFA II standards for these products.

Under PDUFA II, the goal is to review and act on about 85 percent of complete blood bank and source plasma BLA submissions or 90 percent of BLA submissions within 12 months after the submission date. In practice, although we receive a lot of submissions, with a limited staff, I think our average time for turning around something like a PAS ranges between six to eight months. So we are well ahead of these goals. We have never even come close to missing one of these voluntary goals.

So that is the general expectation.

I think one take-home message, if nothing else, from this workshop is that your highest likelihood of having an approved application in the shortest amount of time is to come in with a high-quality application. That is very predictive. Particularly from an oversight management standpoint, where there are multiple sites involved, the more consistency and high quality of applications, the faster things will go through the process.

What are some of the elements of managed review? Some of these are unique to our office. Some of them are CBER-wide.

We have instituted milestones for the review process. An important one that we use is called mid-cycle review. If you submit an application for which we have a 12-month or a 90-day timeframe for review, the midpoint of that review period is the time by which we expect that the submission will be substantially reviewed. In other words, each of the discipline reviewers needs to go through that application and identify any key hurdles which would prevent approval of that submission.

In the second half of the cycle, what we do is work interactively with the sponsor to iron out any of the perceived deficiencies in that application and try to arrive, before or at the cycle endpoint, with an approved application.

So the goal is a one-cycle approval, to do the review process, interact with the manufacturer, and not have to go through the process of issuing what is known as a complete review letter, which cites deficiencies and then puts the ball back in your court to respond in writing to us. That is our goal. It's a worthy one for you, as well, to be responsive when we do have interactions following that mid-cycle review process.

Another major milestone we have -- I know from signing many of these applications, it's very hard to review an entire application and make sure all the documents are in order, if you have very little time to do that and a number of applications to sign off on in an afternoon. So we have instituted a metric for T minus 10. In other words, that application needs to be put into final order and start submitting for final review signoff 10 days before the target date for finishing that application. That just saves us from compressing everything down to the last few days. It really does result in a higher-quality process on our end.

We have improved reviewer and supervisor accountability. Each of the reviews is signed off by a branch or laboratory chief, who needs to concur with that review or else iron out any differences between management and the reviewer in a systematic way.

We try to adhere to timely final actions and to a quality-assurance program of our own at all steps of the application, including content review, the meeting of timelines, and the completion of the final archival package.

In closing, I will just say once again that the Division of Blood Applications is your primary point of interaction with the blood establishment part of the application process. The CSO assigned to your firm is your primary contact point for calling in. You can get hold of them through that number. Virtually all of our CSOs are here today. We invite you to introduce yourself and start establishing a working relationship if you don't already have one. I expect many of you do.

We look forward to a successful workshop and hearing from those of you who have had successful experiences with submissions, defining some of the best practices associated with those submissions, and also from our colleagues who actually manufacture the devices, which are critical, of course.

Thank you, and thank you all for coming.

MS. FIELDS: Thank you, Alan. That was a very comprehensive review of the regulations associated with the licensing process, and also the managed-review process, which a lot of people from the blood banks and blood centers are not aware of.

The next speaker today is Ms. Judy Ciaraldi, who will be presenting an overview of the review process that we do at the Division of Blood Applications for the apheresis products.

Ms. Ciaraldi is a consumer safety officer at the Division of Blood Applications, the Blood and Plasma Branch. She actually holds two BS degrees from the University of Maryland, one in biology and one in computer and information sciences. She has worked as a blood bank medical technologist, a blood bank educational coordinator, and an assistant supervisor at the Washington Hospital Center in Washington, D.C., for about 25 years before coming to FDA.

At FDA, she has been very involved with the blood and plasma review duties, as well as with the inspection process. She also is the trainer for the field inspectors that are deployed from the Division of Blood Applications. She has also won numerous CBER and FDA awards.

It's my pleasure to present Ms. Judy Ciaraldi.

Return to Table of Contents

Agenda Item: FDA Review of Apheresis Submissions

MS. CIARALDI: Good morning, and thank you very much for attending.

It's nice to know that some things are still free. We welcome your attendance at this workshop.

I am going to explain what goes into our review of apheresis submissions. I am going to do this by listing the resources that we use for our reviews, introducing you to our review checklist, going over the general content of apheresis submissions, and then drill down to more specific content for specific products. I will tell you how to ship products to CBER, and then I will explain the comparability protocol submissions.

We base our reviews on regulations in the CFR, recommendations in FDA guidance documents, device operator manuals and package inserts for reagents and supplies, and published scientific literature. I am going to go into more detail for the first four items.

These are the regulations that we use for our apheresis review. It's not an all-inclusive list, but they are the ones that pop up most often during our reviews. I am going to spend a little bit of time highlighting a few of the regulations in each of the sections.

Under donor selection:

640.3 contains the general donor suitability criteria, information such as the vital sign requirements and hemoglobin/hematocrit criteria.
640.21 contains additional information for apheresis donors.

Under collection procedure:

640.4 says that collection must be done by a trained staff, that there must be records kept of the collections, there should be positive identification of the donor, and arm preparation should be done to prevent contamination of the final blood component.
640.22 talks about apheresis collections.

Under testing:

610.40 contains requirements for infectious disease testing.
640.5 talks about testing for group and type.

Under product standards and quality control:

600.15 contains the requirements for shipping blood components, the shipping temperatures.
610.53 contains the requirements for storage and storage temperatures of the different blood components, as well as the expiration dates.

Under labeling:

606.121 has the requirements for the contents of the container label.
606.122 has the minimum contents for the circular of information.

Under GMPs:

210.1 says that if a manufacturer fails to comply with good manufacturing practices, FDA considers the product to be adulterated, and the manufacturer could be subject to regulatory action.
211.22 talks about the quality-control unit and their responsibilities.

Lastly, under submission content, 601.12 -- Alan talked about that, so I won't go into any detail.

These are the GMP regulations that we use for our reviews. Again, it's not an all-inclusive list. I am just going to spend a few moments going over some examples in each of them:

211.25 and 211.28 say that the staff and the supervisors must be trained in their responsibilities.
606.20 says that there should be sufficient numbers of staff and that they, through education and training, must have a thorough understanding of their activities and responsibilities.

Under equipment, supplies, and reagents:

211.68 says that automated electronic, mechanical, and computer systems must be calibrated and checked according to a written program.
606.60 says that equipment must be standardized and calibrated on a regular basis to ensure that they perform as they are designed to.
606.65, for supplies and reagents, requires you to follow the package insert.

Under SOPs:

211.100 says that you must have written SOPs and you must follow them. If you need to deviate for any reason from the SOPs, this deviation must be justified and documented.
606.100 says that SOPs must contain all the steps of a manufacturing process. They must be available to staff in the area where the work is performed. You are required to review records before products are distributed. If there is any discrepancy, you are required to thoroughly investigate it and document this investigation.

Under lab controls:

211.160 requires you to establish specifications to determine the acceptability of your product. This procedure or process should include a sampling plan and procedures. If, again, you need to deviate from any of the specifications and procedures you have set up, you need to justify it and document this in writing.
In 606.140, it says that your standards must be scientifically sound and you should have SOPs for monitoring the accuracy of your procedures and your devices.

Under records:

211.186 says that the records must be dated and signed by the preparer of the record and checked and dated and signed by a second person.
211.192 says that the records must be reviewed by the quality-assurance unit, and if there are any discrepancies, they must be investigated.
606.160 says that you must maintain your records concurrently with the performance of your activities, and the records need to identify the date when they were created and the person who created that record. They need to be as detailed as necessary to show a complete history of the work that was done.

Lastly, under adverse events:

606.170 says you must maintain an adverse-event file and you must report fatalities of donors or of patients, where that death is related to a transfusion, to FDA.
606.171, which you are all familiar with, is the biological product deviation report regulation.

Besides regulations, we also use guidance documents to base our reviews on. The guidance documents on this particular slide can be found at this Web site. I am going to just briefly go over the contents of each of these guidance documents.

The first one, which is for automated RBC collection, contains information about the validation procedures, quality-control procedures, the recommendations we have for these; also information about donor suitability and how to send in a submission if you want approval for a license for automated red blood cells.

The next one is for the sterile connecting device. It contains information on when it is appropriate to use this device.

The next one is our intrepid plateletpheresis guidance. It contains information on donor suitability and product quality control.

Lastly, the guideline for quality assurance talks about the scope and content of a quality-assurance program. Again, it's only the minimum scope and content. You would probably have to adjust it for your own needs.

This slide contains our labeling guidance documents.

In the first one, we recognize the ISBT as an acceptable standard for our machine-readable requirement. In this particular one -- it's our second one out recognizing an ISBT standard -- this specific one recognizes the new guide, the 2.0.0 guide for ISBT.

The next one contains information for blood and blood component manufacturers about how the barcode regulation applies to these products.

After that, it's the guidance where we have accepted the AABB circular of information as an acceptable labeling to meet the regulations in 606.122.

The last one here is our guidance for recognizing the Codabar labeling standard.

This slide contains guidance documents to help you submit your application or your supplement to FDA. I am going to start with the bottom one first. This is the one that Dr. Williams went over that describes how to submit an original application for a license, but it also contains general information for the content of a supplement, if you want to change that.

The top one, as he also talked about, contains information for licensed manufacturers who want to in some way amend that license -- change it to do something different from the way they were originally approved.

These are additional manufacturing guidance documents. I want to point out that they are found on a different Web site, this one that contains our old blood memoranda.

The first one is for the licensure of leukoreduced products. It contains information on product standards and how to send in information if you want approval for this.

The next one is for infrequent plasmapheresis donors. It contains a description of what this is and how to submit to FDA.

The next one is for the red cell loss during source plasma collection. Even though this is specifically titled for source plasma, a lot of the content of this has been seen in operator's manuals for collecting other products.

Lastly, the volume-limits guidance document is our guidance document of our nomogram. While the title says "Source Plasma," we have seen that a lot of operator's manuals do include the FDA nomogram. I wanted to point that out.

The last set of guidelines that I will go over, or guidance documents, are the ones that we reference for validation procedures.

The first one is for the validation of software. It includes a small section on on-site user validation. It can be found on the CBER Web site.

The next one is for general principles of process validation. This can be found on the CDER Web site. So that is a little bit different, but it is out there for us to use. It was a joint guidance document prepared by CBER and by CDER, but CDER has posted it on its Web site instead.

We also rely on operator's manuals and package inserts for the information that we don't have in our regulations or have in our guidance documents. Examples of operator's manuals or PIs, package inserts, are the ones that accompany apheresis instruments, sterile connecting devices, platelet and white cell counters, collection bags, and leukoreduction filters. This, of course, is not an all-inclusive list.

We use the operator's manuals and package inserts to get information on donor selection, collection and processing procedures, and product specifications. Just as an example, we will use the package insert that comes with a collection bag to determine what the volume capacity is for that bag, because you are not allowed to exceed that limit. Secondly, we will look at that same package insert to see what the storage temperature and the shelf-life is for product stored in that bag.

So that is just an example.

These are details that are not contained in regulations or in guidance documents, and they are unique and specific for each supply or each apheresis instrument. These are valuable documents to reference.

We used all of the documents and all the regulations that I mentioned and put it all together and created our apheresis review checklists. These checklists are located on the CBER Web site at this link. I am going to introduce you to what is available there. They are actually available in the handouts right behind my talk.

We have one for apheresis red cell review, one for leukoreduction, plateletpheresis review, one for infrequent plasma collection. We have ones for SOP and labeling, talking about the minimum content of these, and ones that talk about the minimum content of a quality-control form.

We also have individual checklists that are based on each device manufacturer's directions or specifications. The ones that are posted on the Web are listed on this slide.

I want to let you know that, while it is not listed on the slide, we are prepared to review submissions for the Haemonetics Cymbal device.

We use the checklists to ensure a complete, correct, and consistent review. That way, everybody is being reviewed against the same standards.

The lists that are on the Web were current at the time that they were posted, which is October 2006. But these that are posted may not represent our current or our future policies. These are living documents, and they are being updated constantly, as we use them in the branch.

Submissions and approvals are site-specific, device-specific, and product-specific. But you can bunch multiple sites and products in one submission, especially if they are all being collected with the same device. After the approval of that initial submission, if you want to implement collection at a different site or you want to use a different instrument or you want to collect a different product, you would need to put a new submission into FDA. But you may be able to streamline this process with the use of a comparability protocol, which I am going to talk about later.

The general content for any apheresis submission is to include:

The FDA form 356h. It is basically a cover letter that helps direct your submission to the proper office.
The cover letter.
SOPs that are appropriate for what you are requesting.
Records and forms, both completed and blank.
Product quality-control logs.
Labeling.
Products (for some submissions, not for all).
You may reference your previously approved SOPs, forms, and labelings, but please include the STN number or the reference number under which those previous documents were approved.

Let's talk about each component of this and go into a little more detail, so you know what to include.

For the cover letter:

It should contain information about the products that you have requested for licensure.
Include the anticoagulants that you are using.
Include whether or not it's going to be leukoreduced or you are going to irradiate it.
Include a list of collection, processing, and testing devices, and identify what they are. That will help tell us if this is a new device or one that we have previously approved that you are just implementing at a new center.
Include the list of blood centers that will be preparing these products. It would be helpful to include the address and registration number, because then we can be very specific about our reviews.
Also include a description of your operator training. You don't need to include the actual training records. We will review those during FDA inspections.

The SOPs that we would like to see to help facilitate your review are included on this slide. These are called our "Big Six" SOPs. I know some of you have heard that term. It's because they cover almost all aspects of the manufacturing process.

Under donor suitability, we would like to see how you determine that a donor is acceptable or unacceptable. It would include your donor-deferral procedures and donation intervals.
Collection procedures include not only how you collect the blood component, but how you prepare the arm and how you monitor the donor for reactions.
Donor history forms, how you facilitate the interview process, including any informed consent that you would do.
The product manufacturing procedures. This is probably one of the biggest sections. It includes quality control, labeling, the splitting of the production, leukoreduction, storage and shipping instructions, equipment calibrations. It could also include use of your sterile connecting device, apheresis machines, and irradiation, if that is something that you are submitting for the first time.
We would also like to see procedures for adverse-event and failure investigation. This would include monitoring and investigation of donor reactions and the quality-assurance oversight program.
Lastly, the quarantine and disposition of unsuitable products.

Under records and forms, we like to see the records that you use and forms for your donor-selection process, including your donor questionnaire, your informed consent, and your high-risk-education materials. Again, if they have been previously submitted to us and they are unchanged at the time of the new submission, you don't need to report them, but reference the submission under which they were previously approved.

We would also like to see records and forms that you are going to be using for processing your product and for doing the collection. Part of the reason we look at blank forms is so that we can make sure you are capturing all the important data.

Next we like to look at your quality-control logs. In some cases these may be blank forms, and in some cases they will be completed. I am going to go into a little more detail on the content of the QC logs.

The completed records and forms that we like to see submitted to us that will help us facilitate your review are two consecutive months of quality control. These are quality control for the apheresis red cells and the plateletpheresis products. These right now are the only ones that we are looking at for quality control.

The quality-control records should represent each device at each center. They should be a sample of all the product types that you are making. For instance, if you are making single and double red blood cells, automated apheresis red blood cells, we like to see a sampling of the singles and a sampling of the doubles. In plateletpheresis, we like to see a sampling of singles, doubles, and triples, depending on what you are asking for in your submission. It should be for each instrument and each facility.

If you also want leukoreduction, those two consecutive months of quality control should include leukoreduced products as well.

Also we want to see, not your whole validation data, but just a summary of the results of your validation. That should include failure investigation that you have done if it was needed.

The type of information we feel is important to be included in your QC logs:

The product description, such as the name of the product, whether or not it is leukoreduced.
The type of collection (a single or a double, for instance).
Collection and testing dates.
Product specifications.
The product testing results, such as the white cell counts, platelet yields, absolute red cell volume, the pH, red cell recovery, product volume, and so forth. Again, that is not an all-inclusive list.
We would also like to see notation of the collection device, identify which one is involved in that quality control.
Product identification number, collection, which is your unit number.
The collection center where this quality control took place.
The identification of the person who performed the quality-control testing.
Evidence of quality-assurance oversight.

Some of the submissions may need to have labeling sent in.

If that's the case, you will also be asked to include a Form 2567. It's basically a cover letter for the labeling submission. It is returned to you with the results of the label review.
A circular of information should be included, unless it has been previously approved.
A base label, with product overlay labels for each product that you are requesting approval for.

Our newest revision to our labeling regulation is one that requires certain information on the label to be machine-readable. This is the unique facility identifier, the lot number, the product code, and the group and type of the donor. These all must be in a machine-readable format.

We have recognized two labeling standards that meet this particular requirement: the ISBT 128 and the Codabar. If you want to implement the ISBT, you must request a variance, a 640.120 alternative procedure to 606.121(e)(1)(ii). The reason for this is that the ISBT labels have the anticoagulant in a different position from what is specified in the regulations. So to use ISBT, you would have to deviate from the regulations and get approval for that.

Also what is unique to apheresis products is that the term "apheresis" is included within the product name or the attribute section of the label. To get specific, in Codabar labeling format, they term "apheresis" as an attribute to the red cell label, and right now only to the red cell label. The word "pheresis" is included in the plateletpheresis label.

Under ISBT, the term "apheresis" is a modifier in front of all product names.

Let's spend some time talking about the specific products and additional information that we would expect to see in a submission for that particular product.

The type of information we would expect to see in SOPs for the apheresis red cells would be information about donation interval between apheresis red cell donations. After donating one unit of red cells, with or without platelets and/or plasma, we would expect to see an eight-week deferral, and after donation of a double-unit red cell collection, we would expect to see a 16-week deferral.

We would also expect to see information about deferral for red cell loss during an incomplete procedure. If there has been less than 200 mL of red cells lost during the procedure, there is no deferral required or recommended. However, if there is a second red cell loss within eight weeks, deferral will probably be needed. If it's less than 100 mL within an eight-week period, the deferral would be eight weeks from the second red cell loss. If the red cell loss is 100 mL or greater, and again it's within the eight weeks, we would expect to see a 16-week deferral from the second red cell loss; if the red cell loss is between 200 and 300 mL, an eight-week deferral; and more than 300 mL, a 16-week deferral.

Our guidance document for apheresis red cells recommends two testing protocols, one for initial validation and one for monthly quality control.

For the validation, or what is in the guidance document identified as a Phase 1 testing, we recommend 100 consecutive units from all devices at the site, to include single and double red cell collection. We mention in the guidance that you can use both units of a double red cell collection to count towards the 100. We have recommended in the guidance document that 95 percent meet the product standards or, again, we recommend that you repeat the validation to assure that you are making product that is consistent with product standards.

For monthly quality control, two months of which are included in your submission for this product, we recommend 50 units at each site, to include single and double red cell collection, in all devices at the site. We recommend in our guidance document that 95 percent meet product standards or repeat the quality control to identify the problem.

Some firms have told us that this may be burdensome to their sites. They have asked if they could send in an alternative approach or procedure. For guidance documents, recommendations in guidance documents, you are certainly allowed to do that. If you want to revise your procedures to include a different testing paradigm, please contact your consumer safety officer. We will review it to determine if it's better than, or at least equivalent to, the one that we have recommended, so that there is no impact on the safety, purity, and potency of the products that you are manufacturing.

What we would expect to see in the SOPs for plateletpheresis is information about the donation intervals. Plateletpheresis can be collected every 48 hours, but no more than twice in a week and no more than 24 per year.

Also, after a 450 whole blood loss during a plateletpheresis procedure, we would expect to see an eight-week deferral, unless the extracorporeal red cell loss is less than 100 mL. The maximum red cell loss per year should not exceed the red cell loss that is allowed for a year's worth of whole blood donations.

For determining if a donor is eligible to be a plateletpheresis donor, you may use a pre-donation platelet count of 150,000 platelets/μL or greater. You may also use post-count from the previous donation or as directed by your device operator's manual.

For your submission for your plateletpheresis, you should include a summary of your validation and any sterility testing that you have performed during this validation. That should be included within the summary for the implementation validation.

The plateletpheresis procedure requires a monthly quality control, two months of which is included in your submission. The quality control is four units per machine type, per product type, at each site. Per product type -- the way that we identify this is, if you are collecting singles, doubles, and triples, we would expect to see four single units, four doubles, and four triples. The platelet counts should be greater than or equal to 3 x 10 11, with 75 percent of the products tested meeting this standard. The pH should be greater than or equal to 6, with all the units meeting this standard. You records should include the product volume.

The quality control can be done at the expiration of the plateletpheresis or at time of issue. We ask that you test one unit of a multiple-bag collection.

Let's go on a little bit more about plateletpheresis, the newest product, the 7-day plateletpheresis.

We have currently approved two systems for 7-day storage of plateletpheresis products, the Gambro and Baxter systems that you see on this slide. Products from both of these systems must be tested with the BacT/ALERT microbial detection system using both the aerobic and the anaerobic bottles. The particular type of product that can be prepared for a 7-day is the leukoreduced plateletpheresis only. Approval is required before you distribute the product.

Licensed firms requesting this product need to request an exemption to 610.53(c) under the provisions of 610.53(d). Unlicensed firms requesting this product need to request an alternative procedure to 610.53(c) under 640.120, the variance regulation that Dr. Williams mentioned. The reason for this is that currently the regulations only allow a five-day expiration date for platelets and plateletpheresis. Therefore, to go beyond that, you are deviating from the regulations and you need approval for that.

Both licensed and unlicensed firms should participate in a post-market surveillance study. Both should submit SOPs for us to review, and both should submit data to FDA one year after the approval.

Licensed firms also have to submit labels and products to CBER.

These are the review criteria if you want either the red cells or the platelets that you prepare by apheresis techniques to be leukoreduced. The product standards are greater than or equal to 85 percent product recovery, the platelet recovery or the red cell recovery. The white cell count for the plateletpheresis and for the red cells has to be less than 5 x 10 6 white cells per container. If the collection container itself meets the standard, less than 5 x 10 6, you don't need to collect any baby bags or the split bags that you prepared. However, if the collection container is greater than 5 x 10 6, you should do an investigation to determine where the process failed. If you still want to give those baby bags, you should count each individual baby bag. If the count of any of them is less than 5 x 10 6, then you can label those bags as leukoreduced for distribution.

If you want to get approval for this, you should submit two months of quality control, but you should continue to perform quality control:

One percent of your collection, or four units if you prepare less than 400 units per month.
Test each product type each month.
Ninety-five percent should meet the product standards or another standard that is specified by the device manufacturer.

One reminder: If you want to submit and prepare products for leukoreduction and apheresis products, you should follow the appropriate guidances. In other words, if you want to prepare leukocyte-reduced apheresis red blood cells, both guidance documents should be used and followed, and become part of your SOPs. If you want to prepare and submit for licensure the leukoreduced plateletpheresis, again the plateletpheresis guidance and the leukoreduction guidance should be included within your manufacturing process.

What we would expect to see in the SOPs for fresh-frozen plasma collected by apheresis is the collection volume. Most often we see the FDA nomogram, partly because that is included in a lot of the operator's manuals for the devices. The maximum amount of plasma collected per year should not exceed the following requirements: If you are less than or equal to 175 pounds, 12 liters, and if you are greater than 175 pounds, 14.4 liters. That is the annual plasma loss.

The collection volume should also not exceed the capacity of the bag.

If you choose to incorporate an infrequent plasma-collection procedure, you must request this as an alternative procedure to 640.3(a), under the provisions of the variance regulation. This is because these donors donate plasma every 28 days or less frequently, but they do it without undergoing a physical exam or having their total protein measured. That is what the exception is for.

The guidance document for this recommends that the donors who undergo infrequent plasma collection have a donor weight of at least 110 pounds.

If you want to collect plasma on a frequent basis, more frequent than every 28 days, you must follow the donor criteria for the source plasma donor, which is included in 640.63 and 640.65.

FDA inspections are another important part of our review process. They are done for centers that are applying for a brand-new license, a license applicant with an approved apheresis program, but they are collecting product at an additional or a new site, and as requested by us go facilitate our review.

They are done to confirm that the center is in compliance with the laws, the FD&C Act and the PHS Act, regulations, and commitments made in the submissions.

Let's go on to a new subject, and that is the comparability protocol.

What is it? First, it's described in our regulations under 601.12(e). It is an extension of the regulation that Dr. Williams described in reporting changes to a license application. It is an option for a submission. By no means is it required. It is an option that you may employ.

Specifically, it is a highly specific, well-defined plan for implementing a specific change in manufacturing. It is specific for that change and it is specific for the specific applicant or manufacturer. A comparability protocol is not appropriate for all changes, as we will learn in a moment. But once you get your comparability protocol approved, you may be able to implement that same change at additional sites, but do it in a reduced reporting category. That will allow you to ship products much sooner than if you submit everything using the original reporting date.

It is used if the product manufactured using that change will meet approved product standards, if the manufacturing process has been validated and all equipment has been qualified, and if appropriate validated assays are available to determine the effect of the change on the product.

The reason that all these things must be in place is that we need assurances that products that are being reported in a lower category meet the same safety, purity, and potency standards as a product that has been reported in a higher category.

The most common use for a comparability protocol for blood and blood components is implementing a single change in multiple locations that are operating under the same license, using the same SOPs, forms, and labels that were approved within that comparability protocol.

When should a comparability protocol not be used?

It's not appropriate for a broad plan covering every conceivable change. Remember, it must be specific.
Also if the change has a potential to adversely affect the product. Remember, anything that could have a major impact or, on a major scale, adversely affect the product needs to come in as a prior-approval supplement.
If pre-specified acceptance criteria are not available to determine the effect on the product, we would not expect to see submissions like these as a comparability protocol.
If the change results in a newly defined product that hasn't been evaluated by FDA, then again, that is something we would not expect to see.
Use of a new manufacturing facility that needs to be inspected.
A change in process, equipment, or a facility that may need to be inspected would not be an opportune submission to come in as a comparability protocol.

Submit your original comparability protocol, or CP, as I am going to call it, as a prior-approval submission. Once it is approved, it must be implemented exactly as it is described in the comparability protocol. That is the way we approved it; that is the way we have agreed that it could come in as a lower reporting category. Subsequent supplements reporting implementation of the change described in the comparability protocol may be reported in a lower reporting category. We will include which category is most appropriate in our approval letter. The most common downgrading is from a prior-approval supplement to a CBE-30. As Dr. Williams described, on a CBE-30 supplement, you can distribute a product within 30 days if you don't hear from us that there are problems with your submission.

The subsequent supplements reporting the implementation should include all the information committed to in the approved comparability protocol.

If we determine that the subsequent submission that has been reported in the lower reporting category has been implemented in a manner that is not consistent with your approved protocol, we will most likely require that all future submissions reporting that change would have to come in as a prior-approval supplement. In other words, if you don't comply with your approved comparability protocol, you will lose the advantage of having it and submitting it, which is to get the lower reporting category.

If you have a new comparability protocol, again those would come in as a prior-approval supplement. If you change an approved comparability protocol, you should discuss this with us, because we don't know what the impact of that change would be on the safety, purity, and potency of the product, and we will probably have to review it and determine if that change will require a different reporting category.

The general contents of a comparability protocol submission:

It should include a description of the change, what you want to implement in the future under the lower reporting category.
It should include your full implementation plan, including a description of your training.
Specific tests and validation protocols, such as used to determine the impact on the product that you are making.
Product acceptance criteria.
The supportive data obtained from the testing and the validation.
Your quality-control testing procedures, including your sampling plan for that testing.
A description of actions that you would take if the acceptable results are not achieved -- in other words, your failure investigation procedure.
Your quality-assurance program oversight of this manufacturing process.

To go on to the next topic, for some products, we do require that they be sent in to us as part of your continuation of your review. The products so far that we are asking to be sent in are the plateletpheresis products.

Ship the products for the following situations:

If you are applying for a brand-new license, we would like to see the platelets to determine if you are making the product according to recommendations, requirements, and according to the product standards described in operator's manuals.
Centers that have an approved license but they are supplementing it to newly include apheresis products.
As requested by us to facilitate our reviews.

The products should be shipped after you have completed your validation and your two months of quality control. They should be sent after you have completed all the testing and the labeling of the product.

Before shipping products to CBER, call the Laboratory of Cellular Hematology in the Division of Hematology, at (301)827-3413, to schedule your shipment. The lab is open from Monday through Friday between 8:30 and 4:00, excluding federal holidays.

Follow your existing SOPs for collecting the product, processing and testing it, for packing and shipping it to anyplace that you might ship any other products intended for transfusion.

The product should arrive at the laboratory during operating hours and before they expire. To ensure this last particular requirement, the product should not expire on Friday or Saturday. It's a good idea to include the reference number or the STN number in the documentation with your platelets so that it can be traced to the proper submission. Also include all the information that we have listed for the content of the quality-control log.

Send products to this address. I won't read it; it will be on your slides.

If you want us to return any of the shipping boxes or coolants that you sent us, please include a prepaid, self-addressed shipping label with your platelets.

In summary, CBER reviews are based on regulations and guidance documents, operator's manuals, and package inserts. Your submission should contain enough information for us to do a substantive review. If it's not complete and not accurate, it could delay the approval of your submission.

Merilyn Wiler was just talking to me about this before I came up for my talk. She said, "How much is enough? How much should we include in the submission?" As a general statement, what I can answer to that is that you have to not make any assumptions about our knowledge. In other words, a lot of us come to the branch with different backgrounds. Don't assume that we have performed these procedures on a regular basis. Some of us have; not all of us have. You should be writing your documentation for an outsider to read and understand. That will tell you how much information should be included.

Consult our checklist and your operator's manuals and package inserts for specific information and standards that should be included in your submission.

Some reviews may require platelets to be sent in to us for testing and some may require facility inspections.

A comparability protocol is a submission option. It's something that you may elect to do if you want. It may allow implementation of the change that is described in the comparability protocol in a reduced category. The CP must be implemented as approved. If you have any changes in your approved CP, please contact us as soon as possible. It's not appropriate for all types of submissions.

The approvals are specific for the apheresis instrument, the products that are collected, and the collection facility.

If you want more information, you can write us at this address. You can also call us at (301)827-3543 or fax us at (301)827-3534. You may also speak to the consumer safety officers in the Blood and Plasma Branch.

I am proud to introduce you to the Blood and Plasma Branch consumer safety officers. I am also proud to consider them my colleagues in this branch. I would like to ask all of them to stand and remain standing until we are all done. That way, it will give everybody a chance to see who you are and where you are sitting.

Karan Blum. I am already standing. Marla Cohen will start next week. She is brand-new. Lore Fields you have already met. Diane Hall is in the back. She is also brand-new to us. Jennifer Jones, another new employee; Rosia Nesbitt; Faye Vigue. Faye is recovering from surgery. I wasn't sure if she was going to make it. Cecilia Watson is manning the fort back at the office. Hoi May Wong; Monica Yu; Ken Zemann, our elder statesman. Our acting branch chief is Dr. Les Holness.

One other important individual is not on this slide, but I want to tell you how important she is. We do rely on her for a lot of guidance. That is Ms. Elizabeth Callaghan, acting division director.

Thank you very much for being part of my branch and working with me. Thank all of you for attending this workshop.

MS. FIELDS: I just want to thank Judy again. That was a very thorough review of our review process in the Blood and Plasma Branch.

We began posting these review checklists on the CBER Web site about a year ago. I think it has really made an impact on how the apheresis submissions are coming in and allowing industry to really understand our thought processes behind how we do the review.

The other key point that Judy brought up -- she explained a lot about the CP process. I think that is something that a lot of people can take advantage of that will streamline the review process.

We are actually running a little early. I can't tell you the last time that that happened. But I did ensure that they do have all of the refreshments out in the break area. Maybe we could return here at 10:00. That will give us 20 minutes.

Thank you.

(Brief recess)

MS. FIELDS: I would like to make a few housekeeping announcements.

[Administrative announcements]

The next speaker today is going to be Rosia Nesbitt. Rosia is going to be outlining some of the issues that we come up with when submissions come in. Basically, the whole group in Blood and Plasma got together and we came up with the top 10 reasons that we find problems with submissions. She is going to go through all of them. I think it will be a good learning lesson for everybody. As you are going through, you can make sure that your submission, right before you send it in, doesn't contain any of what we are calling pitfalls.

Rosia Nesbitt is a consumer safety officer in the Division of Blood Applications in the Blood and Plasma Branch. She has been with us for about two years. Prior to that, she worked as a reference laboratory technician, a regulatory affairs associate, a manager and an error/accident regulatory person at the American Red Cross, and a senior regulatory affairs associate at Blood Systems. We stole her.

Ms. Rosia Nesbitt.

Return to Table of Contents

Agenda Item: Top Ten Pitfalls with Submissions

MS. NESBITT: Good morning.

Judy has reviewed what should be included in a submission. My topic is "Top Ten Pitfalls with Submissions." These pitfalls are what we have observed in prior submissions to CBER. These pitfalls are not in any order or according to rank or weight. All of these pitfalls could potentially be the number-one pitfall.

I will list the top 10 pitfalls first and then I will go back and go into more detail on each one of the pitfalls.

The 10 top pitfalls with submissions:

Donor informed consent and applicable SOPs do not include all possible adverse reactions cautioned by device manufacturers.
Applicable SOPs are not submitted with the application.
SOPs are incomplete.
Failure investigation SOPs are either incomplete or they are missing from the submission.
Quality-control data in the submission is either missing or inadequate.
Quality-control forms are incomplete.
There are general content problems that we see.
Comparability protocol content problems and subsequent submissions.
Label submissions are incomplete sometimes.
Platelet product submission problems.

Donor informed consent and applicable SOPs do not include all possible reactions cautioned by device manufacturers. The following are often not included in the informed consent: anxiety, allergic symptoms, unusual taste or smell.

Donor adverse events unique to apheresis should be included in the informed consent and are often missing. Certain manufacturers require additional recommendations. For example, improper operating conditions may cause complications such as blood loss, hemolysis, air embolism, and blood clotting. If you are using a device from a manufacturer that makes these recommendations in their operator's manuals, your informed consent should reflect these recommendations.

Applicable SOPs are not submitted with the application. SOPs that have an impact on the manufacture of the components being requested for licensure should be included, such as your quality-control SOPs, failure investigation SOPs, donor reaction SOPs, approved SOPs that have undergone major revisions. These SOPs are vital when we are reviewing submissions. When SOPs are missing, this slows down the review process. Please note that previously approved SOPs do not have to be submitted unless they have undergone major revisions. However, the form needs to reference the previously approved submission tracking number if you are submitting previously approved SOPs.

SOPs are incomplete. SOPs, including donor deferral criteria, are often lacking pertinent information, such as deferral information for red blood cell loss. Judy has already talked about red blood cell loss deferrals. If you need to, refer to her slides for the appropriate deferral category.

SOPs do not state what to do with platelets, pheresis, or red blood cell components that have been flagged for QC by the collection device for possible leukocyte reduction problems. The SOP should clearly state what to do with the product. Should the products be relabeled as non-leukocyte-reduced or should they be discarded?

The SOPs for component collection do not contain all of the operation specifications described in the device operator's manual, such as the type of sample, timeframe for performing WBC and platelet counts, what to do if the timeframe for testing is not met. I would caution you here that the firm should be very careful about paraphrasing steps from the device manufacturer operator's manual, because important steps in the process may be left out and the intent of the SOPs may be missed.

Reference in your SOP to follow the operator's manual is acceptable. However, the firm should be aware that if they are relying only on the operator's manual, it may not be as thorough as an SOP. For instance, the operator's manual may not have all information for GMPs, such as documentation.

SOPs describing monthly QC do not always include random or representative selection. The SOP should state that the product for QC should be randomly selected and that each product type should be represented.

Time limits for testing: Your SOP should state the time limit that your product should be tested, whether it's within 24 hours, 48 hours -- whatever the time limit is. Your SOP should reflect that.

Your SOP should reflect the acceptance/rejection criteria -- what is acceptable, and when that product is not acceptable, that it should be rejected.

The disposition of unsuitable units: Your SOP should state what you are going to do with the unsuitable units if they are not within the acceptable criteria.

Failure investigation SOPs often do not include when to initiate a failure investigation or root-cause analysis. Failure investigation SOPs often do not include methods for investigation and correction. How to handle and investigate failures should be clearly stated in the firm's SOPs, so that when a failure does occur, staff will know exactly what to do. Later on today, Hoi-May will cover failure investigations.

Quality-control data in submissions is either missing or inadequate. Monthly QC data for platelets, pheresis does not always include the required collection per machine type, product type, per site. Judy has in her talk this morning discussed what that monthly QC data should include.

Oftentimes, the two consecutive months of QC data are not submitted with the application. Monthly QC data for apheresis red blood cells do not always include 50 units per site with at least one single component included. Oftentimes, we see your monthly QC data and it might have all double products. We need to see at least one single product in that.

The measured total volume is not within the volume limits.

Another example of inadequate QC data is that sometimes the firm requests approval for single, double, and triple platelets. However, the QC data only reflects single and double units. Remember, your QC data should reflect what the firm is requesting approval for.

When the QC data is missing or inadequate, the firm is contacted and requested to submit additional QC data. This in turn slows down the review process.

Monthly QC forms do not include all of the required information. Your firm should state the facility you are requesting approval for. Oftentimes, when there is a facility that has multiple facilities, you see the main facility on the QC form, but they are requesting approval for one of the other facilities. You need to either write that facility on the form or stamp it on. The facility name should be on the form that is requesting the approval.

I know sometimes the blood unit numbers can tell you what the facility is. But if that is the case, you need to have some type of legend for us to know.

Your QC forms should have device manufacturer and type. It should have your blood unit number, date of collection, date of testing. That is exactly when that test was performed, whether it was the WBC count or platelet count or whatever. It should have appropriate collection types, whether it's for a singles, doubles, or triples, or for singles only, doubles only.

On your QC form, you should have interpretation of results, whether your QC passed or failed, was satisfactory or not satisfactory. You should have your yield on there, what the acceptable criteria are. That should be on the form, so that people that are reviewing can just look right on the form and know that it either passed or did not pass. The initials of the person who is performing the test should be on your QC form. You should also have evidence of review by a second person that has reviewed that form, and records of calculation. This does not necessarily have to be on your QC form, but it should be in your submission packet, so we can see that the calculations were done appropriately.

If you are using a summary sheet, copies of the raw data should be also included.

General submission content problems:

Oftentimes we get submissions that do not include the 356h. The 356h should be included with each submission.
The cover letter does not accurately or clearly state what the firm is requesting. For instance, if the firm is requesting approval to manufacture platelets, pheresis, leukocyte-reduced, singles, doubles, and triples, all three should be listed in your cover letter. Oftentimes we see where the firms, in addition to the singles, doubles, triples, want infrequent plasma, but they never ask for that. Your cover letter should clearly state the reporting category of the submission, whether you are submitting your request as a PAS, a CBE-30, whatever your reporting category, or comparability protocol, if you are requesting that.

When your cover letter is incomplete, we call the firm and we ask you to submit another cover letter requesting exactly what your approval is for.

Comparability protocol submissions often lack:

A summary of validation, including performance/acceptance criteria.
A summary of results.
A description of actions taken if acceptable results are not achieved.
Proposed change in reporting category.
A description of training.
Subsequent submissions do not refer to the approved STN number. For instance, if you are requesting a change to an approved CP, you should reference that STN number of the approved CP, so we can easily go back and look at the original CP.

Label submissions:

Often, your label submissions do not include a Form FDA 2567 when you are submitting your labels. Any time you submit labels, you need to make sure that you include your 2567 with the submission.
Labels lack conformity with the Codabar or ISBT format. You can refer to the guidelines, to uniform labeling of blood and blood components, for the Codabar labels and the United States industry consensus standards for the uniform labeling of blood and blood components using ISBT for your ISBT labels. That should give you an idea of the format that you should be using with your labels.

Problems with product being submitted:

Improper shipment of products to the Laboratory of Cellular Hematology.
Because of the improper shipment, we see that the temperature is not being maintained during the shipping process. They receive the product either too warm or too cold. So make sure that you are shipping your products properly.
Products are not received between Monday and Friday. Judy has already reviewed for us how and when to ship products to the Laboratory of Cellular Hematology.
Products expiring over the weekend. So make sure, when you are shipping your products, that they have a good date on them, so that they won't expire over the weekend.

In summary, this is not an all-inclusive list of deficiencies that we see in submissions. In addition to following the CFR, firms should follow the manufacturer's operator's manuals and package inserts. Submitting a complete application may ensure a comprehensive review in a shorter timeframe.

Thank you very much.

MS. FIELDS: Thank you, Rosia. I think there was a lot of helpful information in that presentation.

Our next presenter is Steve Kassapian. Steve is the director of regulatory affairs at the American Red Cross. He has been there since 1986. He has been in his position for approximately the last 10 years. He is responsible for the preparation, submission, and follow-up of all the license applications and supplements for over 290 of the American Red Cross' facilities. In approximately a 12-month period, his group will submit about 100 applications to the Blood and Plasma Branch.

In 1999, the Red Cross did receive their first comparability protocol. He will be lecturing on how that happened and how that has improved his processes.

Steve received his degree in medical technology from the State University of New York at Albany in 1978.

Return to Table of Contents

Agenda Item: Preparing Apheresis License Submission

MR. KASSAPIAN: Thanks, Lore. Good morning, everyone.

On today's agenda, this section has been billed as "Successful Submissions." How do you define a successful submission? I generally use two measurements for success: number one, limited or no follow-up needed once a supplement is submitted to FDA, and then, of course, number two, quick approval.

Dr. Williams mentioned that approval times average, for PAS, between six and eight months; quick approval, two to three months. That's what we want to get.

Successful submissions are all about communication, communication with the FDA and, just as importantly, communication with your own organization.

The fact is, the process of developing, submitting, and, most importantly, getting approval of license supplement requests is easier than most people think. We use a three-step approach. The first two steps are the same. Steps 1 and 2 are, call the FDA. Call them early, when you first become aware of the need for a license supplement. That's why they are there. In the long run, you will be simplifying the process for everyone involved. Why try guessing at what they want to see in your supplement when you can just ask? By calling early in the process, before you actually begin developing the submission package, you are not only giving your reviewer a heads-up, but you are also ensuring that it will contain all of the appropriate information and that it will be in the format preferred by the reviewer.

Obtaining this information early is also beneficial to your organization's project planning.

Calling early doesn't only mean calling the FDA, but it means calling on the decision makers and project managers within your own establishment. Early involvement within your own organization is critical in the development of a successful submission. Far too often, the submission of a license supplement is the last thought in an organization's implementation plan. That approach will almost certainly cause delays in licensure.

The call-early approach will get and keep you and your organization ahead of the curve. Armed with the information provided by your CSO, you can now get involved with your own organization at the earliest stages of product development. That is the best time to develop the licensure strategy.

Let's use the example of triple platelets. If you get yourself involved at the very beginning of the project, you will be able to provide your organization with invaluable information about what types and how much data you will need to collect and evaluate, because this is exactly what you have been talking about with FDA. For example, what kind of data are they looking for -- validation data, QC data? How much data do they want to see? In what format should it be provided?

Experience tells me that the answers to these questions usually come as the result of discussions between the blood establishment and the FDA. (Okay, maybe it's a little heavier on the FDA side, but it's still discussion.)

Every submission is truly a case-by-case situation. There is room for an honest difference of opinion. By calling early, you allow for this discussion to happen before you collect data that turns out to be useless. More importantly, you provide FDA with the time to consider your proposals for what you think needs to be part of the submission. This time factor can only help your case.

Finally, once the answers to these questions are determined, the establishment can move forward with confidence, knowing that they will be evaluating the process and collecting the data in a fashion that will expedite licensure.

I have heard it said more than once how unfair it is that different reviewers sometimes have different expectations for the same type of submission. Sometimes there might be very good reasons for this. But that is really not the point. We can hit any target required, so long as it is well defined and not moving. By calling early, you ensure definition of the target.

An additional byproduct of this process may also be to help standardize the guidance provided by the CSOs, because by calling early, you allow them some time to engage in internal discussions on the subject and to reach consensus.

By the way, in this real-life example, ARC received approval to a triples prior-approval supplement for a facility and approval for a triples comparability protocol in less than two months from submission. That's being successful.

The second step in the process: Call the FDA. Call them often. Believe me, they don't mind. They would rather you call them before the submission than have to have them call you after the submission.

What is "often"? "Often" is as many times as needed to ensure that everyone involved has a clear understanding of what the FDA reviewer expects to see in the submission package. It clearly establishes and then reinforces the requirements for the submission, nailing down the target, making it easier and quicker to hit.

I am not suggesting that you make a nuisance of yourself, but keeping the lines of communication open before the actual submission will pay huge dividends. As I mentioned before, quick approval is all about communication. Effective communication will prevent misunderstandings between the agency and your establishment regarding your supplement. As a result, the FDA should only have very minor comments and questions, if any, about the contents of the submission after their review. Usually these issues can be resolved via phone calls, emails, and/or faxes. After that, the approval letter will be on its way to your office.

Just one recommendation. Decide who in your organization is the key point of contact and only allow that person to manage the communication. You don't want 14 different people calling them. They don't want that either.

Finally, the third step is to listen and do. Do what you have agreed to do, and do it perfectly. Follow the directions and guidance you have talked about with your CSO to the letter. Ensure that the required data is complete and accurate. Explain any failures or unexpected results. Describe all failure investigations that were performed. If the explanations are complete and thorough, fine, no problem; an approval will be on its way. On the other hand, missing data, failed data, lack of clarity as to the request and/or information provided will surely cause delays in approval.

Obviously, it is in the organization's best interest to submit an application that is organized, clear, concise, formatted in a way that is easy to understand, neat, and complete.

That is all there really is to submitting a successful license supplement.

To summarize, appropriate content plus expected format yields fast approvals. Put another way, give them what they want and need, in a way and manner they expect, and you will be a happy camper.

Now that we have discussed the approach, let's talk a little bit about the content and the structure of an apheresis license submission. The purpose of this submission is basically to demonstrate to FDA that you can manufacture a product in a controlled manner that will consistently meet predetermined specifications -- that is, to ensure the safety, quality, identity, potency, and purity of the product. You achieve this through your SOPs, validation, QC, et cetera.

If your package can sell this, then you will get your license approval. So what should the apheresis licensure package contain?

Before I go any further, I need to make two disclaimers. First, I am going to be talking about and giving examples of how ARC puts together these license supplements. They are not FDA recommendations, but they do work for us.

Secondly, I am going to be showing a lot of ARC forms as examples. While the forms themselves are copyrighted and shouldn't be used as is, there is nothing proprietary or confidential about the information contained within them. In fact, that's why I am using them as examples.

Finally, as an aside, I am not the artist behind these PowerPoint slides. They are the handiwork of Illeana Rivera. Thanks, Illeana.

So what is in an apheresis BLA submission? Routinely, it includes a cover letter, a Form 356h, and supporting information, called chemistry and manufacturing controls, such as SOPs, labelings, and data, and a summary review of that data. In certain submissions, it may contain additional information -- for example, in a situation where a blood establishment wants to expand the submission to include a comparability protocol. We will talk about that in a little bit.

The cover letter is the backbone of the submission. It tells the FDA what you are requesting, for whom, and where. It acts as a table of contents. The cover letter includes a list of products for which the license supplement is being requested, the location and registration number of the collection center, the location and registration of the testing facility, and the location and registration of where QC testing is being performed.

It may also include a list or summarization of supporting information, which may be attached as enclosures, to substantiate the blood establishment's claims that they can consistently manufacture an acceptable and controlled product.

The cover letter should also reference applicable SOPs and labels previously approved. It may also reference previously approved related product supplements.

In addition, if a facility is a backup laboratory for component or donor screening, the name and address of that facility should be included.

Here is an example of a cover letter ARC might use in a BLA package.

That is the address of the FDA. That can be found in 21 CFR 600.2.
This is the type of category and what we are asking for.
A list of products.
We have some mention of comparability protocol information.
Where they are being manufactured.
A list of attachments.
Some information about validation.
Some information about following manufacturer's instructions and package inserts.
SOPs and when they were approved.
Labels, again referencing the approvals.

As I mentioned, the cover letter should include a list of all relevant SOPs and labels. Relevant SOPs include such areas as donor screening, collection, manufacturing SOPs -- the "Big Six" that Judy was mentioning before.

Obviously, any product for which licensure is being requested should be included in the list of labels. If a blood establishment has multiple facilities or has a previously approved comparability protocol for the products for which licensure is being requested, chances are good that these SOPs and labels have already been submitted and approved. If so, simply include the STN number and the date of the approval as part of the list.

Otherwise, if the SOPs and/or labels are new or have been revised since last being approved, include them as part of the submission package itself. Remember, if you include labels, you must also include a Form 2567 for each label.

This is the Form 356h. It must also be included as part of the submission package. It is relatively easy and straightforward. Be sure to include the facility name and address, the product description -- you usually reference your cover letter there -- the type of submission, the reporting category, the reason for the submission, and you should also include any relevant cross-references, such as the STN of an approved comparability protocol that lowers your reporting category or any other previously approved BLA submissions that are relevant.

All the boxes don't need to be filled in. We put "NA" in the boxes that don't apply, for completeness.

This is page 2. We check off the chemistry section there. We check off "Other." We reference our cover letter and attachments, and, of course, sign and date it.

Enclosures and attachments are probably the most critical part of your submission package. It is this information and data that provides the proof that you have the manufacturing process under control and that you are meeting product specifications. So it stands to reason that this is where many supplements get hung up at FDA. Since these are the documents that demonstrate that your manufacturing process is under control and that your products are meeting stated specifications, it's vital to ensure that these documents are complete and accurate. Review these documents with a critical eye. Your FDA reviewer certainly will.

One of the easiest ways to demonstrate that your process is in control is the use of QC data. Routinely, we provide two months of data in the form of daily log sheets and monthly summary reports. As you are about to see, ARC is big on using forms to provide this information in a consistent and standardized way.

To license products, you usually need to submit two months of QC data. For platelets, that would be pH, color, yield, and volume; for red cells, volume and hemoglobin. For plasma that is concurrent with plateletpheresis, we submit a verification that the displayed volume is accurate within 10 percent of the actual volume and a statement that the volume collected is within the manufacturer's recommendations.

Leukoreduction QC can be either linked to specific products being used for QC or can simply be a statistical sampling of units. We have found that statistical sampling preferable because the platelet QC and the leukoreduction QC are performed at different times in the manufacturing stream.

When reviewing QC data, you should ensure not only that the individual data points pass each specification, but that the entire data set is sufficient. In other words, are there enough units, or data points, under the submission guidelines to demonstrate a statistical level of control?

You should also review for appropriate signatures and dating by both staff and quality-assurance reviewers.

This is the platelet QC log that we use that is standardized at all facilities. This log is designed so it can be used to document platelet QC information for singles, doubles, and triples, and for any of the devices that we use. It shows information about the calculation. It includes the acceptable results. It shows whether or not they passed or failed. It indicates who did the work, who reviewed the work. It also provides a space for additional comments.

This is an example of the form that ARC uses to summarize that platelet QC form. Like the platelet QC log, this form is standardized for documentation of the QC data, regardless of the instrument or technology used. We have columns for each of the devices. It includes the acceptance criteria, it shows the cumulative results of the QC data, and it has final sign-off by QA.

This is an example of the red blood cell QC log. It, too, has been standardized and "genericized" to be used by facilities with all technologies and devices. For traceability purposes, this form contains information about the collection site and the type of equipment being used to prepare the components. It also has information about the calculation. It shows the acceptable requirements and whether or not the component passed or failed. It also has final sign-off.

This is a summary form ARC uses for red blood cells. The red blood cell QC summary form is used as a cover to summarize the individual RBC log sheets previously shown. Standardization allows staff to document QC summary data for the three devices used at ARC. Like our other forms, it includes information about the acceptance criteria, calculations and results, the percentage that have acceptable results, and whether or not they passed or failed.

Note that, although all three instruments are apheresis RBC collection devices, their acceptance criteria are not all the same. This form allows for the acceptance criteria of all three instruments to be listed.

This is the counting log for leukoreduced plateletpheresis. This is a form we use to record our leukoreduction counts. It has a similar construct to our other QC logs.

This is the summary form that we use for leukoreduction. Like our other forms, the leukoreduction summary form contains acceptance criteria for the Amicus, Trima, and Spectra apheresis instruments.

At this point, if I haven't totally put you to sleep, you should be noticing a recurring theme. Regardless of what QC test is being performed, we attempt to design a QC log sheet for all devices that reflects the QC process flow, and then we design a summary form to demonstrate the additional control of a quality review. The individual QC forms are designed to flow into the summary report, and it is that summary report that demonstrates the actual control of the process. It's these summary reports that serve as the documentation to demonstrate that the process is, in fact, in control.

So why do we document our QC in this manner? First, we want to demonstrate consistency of process. Second, we want to show consistency of products. Finally, we want to simplify the documentation process. By doing this, we show consistency of the manufacturing process, and therefore have a high level of confidence that we can consistently produce quality products that meet or exceed product specifications.

Validation of apheresis equipment is another critical element in ensuring that manufactured products consistently meet specifications. A summary of the validation performed should include:

Pass/fail criteria.
A summary of the performance qualification showing which instruments were validated, for what products, how many procedures were performed, and the percentage of successful procedures. The performance quality procedures should be outlined in an organization's validation plan by type of instrument.
The validation summary should also include information about any discrepancies noted during the validation process, including a description of the failure and the subsequent investigation and corrective action taken.

The entire validation package should be evaluated to ensure that it is complete and that all of the discrepancies have been addressed. The decision to accept a device for use is made based on the requirements set in the validation protocol and the number and types of failures. Obviously, if the validation needs to be repeated, the submission package should not be submitted until corrective action is taken and the device has been successfully validated.

When validation discrepancies do occur, a complete and thorough investigation is required. An example of a discrepancy would be if a platelet product is collected, everything appears to go as expected, but when the product gets to the QC lab, the yield is only 2.6. What happened? An investigation of a discrepancy of this type is definitely in order. This is extremely important, because, depending upon the outcome of the investigation, a decision must be made as to the validity of the data point, and ultimately about the usability of the device in its current state.

If, for example, the low platelet yield was obtained because the donor was uncomfortable and the process was prematurely terminated, this data point can be discarded and replaced with another one. On the other hand, a platelet yield with less-than-acceptable results where no problem with equipment, donor, or staff was identified can't simply be discarded and replaced with another procedure. It counts as a true process failure. That's why we evaluate each case individually and as thoroughly as possible.

The results of the investigation should be concisely presented in a report, along with an explanation for the resolution.

Validation discrepancies with no impact are usually related to donor or staff issues. In these cases, the procedures are usually discarded and the data point not used as part of the PQ data set. Donor issues tend to be associated with donors becoming uncomfortable for some reason, resulting in the collection process being terminated earlier than expected. Staff issues tend to be associated with not following the procedures.

Bottom line: You want to be able to demonstrate that the equipment is operating as expected and that you have a high degree of confidence that it will consistently do so. This, then, is the justification for moving on to statistical sampling for monthly QC.

This is the ARC discrepancy resolution form. It provides a concise and standardized way for staff to document discrepancies that occur during the validation process. Required information includes:

A description of the discrepancy.
Notification of the vendor or BHQ technical support, if required.
A description of the corrective action.
A conclusion of the discrepancy. By conclusion, we mean a determination as to whether or not the discrepancy may have led to an impact in the collection of products.

The validation summary report provides a means for staff to ensure and document that all aspects of the validation plan were executed properly for each device. This is one of our reviewers' favorite forms. This report identifies and summarizes the facility and equipment, the validation protocol followed, the dates of execution, and the total number of discrepancies. It also includes the pass/fail criteria for the execution.

Page 2 of this form is basically for operational and QA management staff approval. The approval section of the validation summary form is used to document approval by operations and quality-assurance staff. After both groups have approved the data and execution of the plan, it then goes to the CEO of the facility for final sign-off.

Some other supporting information:

Sterility testing. This is somewhat passé and may only be necessary at the initial establishment phase or for a first-time user of an apheresis device.
With regard to submission of product samples, once an organization has an approved comparability protocol for a specific technology, the submission of QC product is no longer necessary. It has actually been quite a while since ARC has submitted products for QC as part of a license application.
Finally, a comparability protocol. This may be used by a blood establishment to reduce the reporting category of subsequent submissions of the same type.

A little bit more about the comparability protocol. When 21 CFR 601.12(e) was first put into the regs, you needed a pretty significant supplement to get an approval for a CP. It's a lot easier today (but we won't tell the FDA). Today we usually submit a comparability protocol along with the first prior-approval supplement for a new technology or product. The comparability protocol basically states that all future submissions of this nature will essentially be identical, because the process and procedure will be the same for the entire organization. Nothing will change or be different. All facilities are expected to submit or request data and information in the same manner.

The comparability protocol may also include other information about such things as internal audits and implementation schedules. But the key elements are that the procedures and processes -- that is, the SOPs -- are standardized, the labels are standardized, the training is standardized. Of course, the beauty of an approved CP is that it allows for products to be shipped across state lines 30 days after receipt by FDA of subsequent submissions.

These are the basic elements of an apheresis BLA supplement. Keep in mind that each supplement is unique, and getting FDA input and guidance prior to submitting a package is the key to success.

Thank you.

I would be happy to take any questions now. Are there any questions?

PARTICIPANT: Do you have a standard template for your different organizations when they send information to you -- here's all the stuff that you ought to put in here? Or are they just the summary reports, like you have here, when it relates to a license submission?

MR. KASSAPIAN: A lot of our SOP and QC documents, the QC SOPs, have the standardized log forms. They send us that information. Generally, we put together the summary forms. In some cases, it's put together by the field; in some cases, it's put together by the regulatory affairs staff. But the log forms are standardized. They are part of the QC SOPs.