Manufacturing

Factor Products: How Factor is Made?

Safety and purity are considered along every step of the factor manufacturing process. For most factor concentrates, the manufacturing process has four basic steps:

1. Sourcing factor

2. Viral removal and inactivation

3. Purification

4. Final formulation

Sourcing Factor

Plasma-derived products come from human blood plasma. Plasma donors undergo strict screening for disease risk factors, and their plasma is tested for several viral diseases. Recombinant products are not derived from blood; they originate from genetically engineered mammalian cells containing the human gene for factor. Recombinants are produced in large bioreactors, with human and animal proteins used in the culture medium in first- and second-generation recombinant factor. Third-generation products contain no human or animal proteins in the culture medium or the final product. Fourth-generation products are made from human cell lines.

Although plasma-derived products potentially risk transmitting blood-borne viruses, all US factor products, whether plasma derived or recombinant, are considered safe by the FDA. (See last week’s blog on purity vs safety to learn more)

Viral Removal and Inactivation

These methods remove or inactivate most blood-borne viruses including HIV, hepatitis A, hepatitis B, and West Nile virus, making them noninfectious. But no viral inactivation method used on factor concentrate can inactivate all viruses. The two most common viral inactivation methods are heat treatment (pasteurization) and chemical

inactivation. Heat treatment involves exposing the factor to a high temperature for 30 minutes to 72 hours, depending on the method.

Chemical inactivation involves mixing the liquid factor in a tank with a solvent-detergent (SD) wash for four to six hours. SD viral inactivation is very effective against certain types of viruses, such as HIV and hepatitis B and C, but is ineffective against hepatitis A and some other viruses. Viruses are also removed by the purification process, especially

immunoaffinity (monoclonal) purification. Viruses can also be filtered from factor IX through a process called nanofiltration.

All plasma-derived products use one or more viral inactivation processes, and so do some recombinant products. Yet other recombinant products use no viral inactivation process. Why? The risk of viral contamination is only theoretical, because the product is not exposed to blood plasma.

Purification

This step separates the desired factor from unwanted viruses, proteins, and other foreign substances, to get the purest product containing only the factor you need. For example, when plasma is processed to make factor VIII concentrate, the serum may also contain von Willebrand factor (VWF), factor I, and other proteins. The higher the listed purity of a product, the fewer the unwanted proteins.

Monoclonal products have a higher purity than intermediate products. Recombinant concentrates have the highest purity of all products.

Final Formulation

Even if the viral inactivation and purification processes create a safe and highly pure product, the final formulation—the way a product is packaged and prepared for market—may alter it. In this final step, other components may be added into the concentrate. For example, albumin is added into the final formulation in the last manufacturing steps of first-generation recombinant products. Albumin helps to stabilize and bulk up the product.7 In second-generation recombinant factor, sugar is added in place of albumin at the final formulation step to stabilize the product. In third-generation products, sugar is added to stabilize the final product, and no human blood component or animal proteins are used in the culture medium.

Why would anyone intentionally choose a plasma-derived product instead of recombinant? After all, recombinant factor is the product recommended by NHF’s MASAC. Why choose an intermediate product and not an ultrapure one? Why inject anything other than the missing factor into your child?

For some people, it’s all about cost. Plasma-derived factor, especially intermediate purity, is less expensive than recombinant factor. People who have high out-of-pocket expenses need safe products, but may choose less expensive ones. Sometimes, the decision depends on the type of bleeding disorder being treated. For example, intermediate purity factor VIII products contain factor VIII combined with VWF (the way it’s naturally found in the blood) and are useful in treating von Willebrand disease.

When choosing your factor, always discuss options with your HTC! Use our factor product guide here, bring it with you, and ask what’s best for your loved one or you.

Local Hemophilia Families Meet the Manufacturers

Local Boston hemophilia families tour a manufacturing plant

I was thrilled last week to invite a group of local hemophilia families to the Pfizer Andover manufacturing plant, where BeneFIX,a  recombinant, third-generation blood-clotting medicine, is made. Andover is only 40 minutes from my house; imagine that this amazing medicine is practically made in my neighborhood! It was a wonderful opportunity for the scientists and researchers there to meet real families, and for the families to see just how blood-clotting products are made.

We were greeted by Bob Duane, Senior Director, Site Quality and Compliance. Families were briefed about their tour, which would be a closed off tour–we didn’t need to get into special outfits to protect the manufacturing process from us and any germs we may have been carrying. But we would get to see how factor is made!
First, we met with a large group of employees, and heard a presentation by Tom Porter, PhD, Senior Director, Analytical Research & Development, Global Biologics, who gave an overview about how factor was produced. He was so enthused about his work; it was refreshing and delightful! He reviewed the history of hemophilia innovation of products from Pfizer, including creating the first recombinant factor VIII product in 1992, which was then licensed to Baxter. I had actually forgotten that little piece of history.
Then each family was invited to stand up and speak a little about their experience with hemophilia. Bob wondered if the families would be comfortable with that and we all laughed—hemophilia families usually have no problem speaking up!
Wendy spoke about having an 18-year-old; Allie spoke about having two with hemophilia (“I win!” she quipped!); I spoke about having a transitioning 25-year-old and our insurance concerns for all in his age group; Carolyn shared about having an 18-month-old; and Diane informed the group that her baby was just diagnosed with an inhibitor. Most special was the speech by Shane, a 12-year-old with hemophilia A, who related that he is learning how to
infuse better to save wear and tear on his veins.

Explaining the process

After a lovely lunch, during which the families were able to sit casually with the researchers and scientists, the group split into two and began their tours. We saw the vats containing the medium in which the Chinese hamster ovary cells produce human factor; learned how it is separated from the medium and then harvested. In the end, product is shipped to Spain to be finished, lyophilized and packaged, ready to be sold. The sheer level of intricacies involved in each step was a bit overwhelming. We walked by many laboratories where staff worked diligently. Everything is breathtakingly clean; most tasks are automated to reduce the risk of human error. We walked on many floors, levels and peered in through large glass windows to see the giant vats where product is made. The families were stunned, at the number of employees required to make product, at the level of safety controls and at the amount of money required to make product.

“It is really fun to see how factor is made and all the work that goes into it. I will definitely think of that when I infuse now,” Shane comented.

“The tour of the Pfizer facility opened my eyes to the extremely long process involved in making factor,” said mother Kathy Secinaro. “It became clear that the staff there are dedicated to research and product safety. In addition to that, they truly showed they care about our community and want to know more about living with hemophilia. I never expected such a genuinely warm welcome.  Others should be strongly encouraged to do a similar tour. I hope to do it again.”

And what did the employees think about the families?

“Yesterday was the best day I have ever had at Pfizer.  I received far more than I gave.”    “I was touched and was amazed at the strength that was displayed by [the families].”   “I was truly inspired by their stories and had such a good feeling all day. I’m looking forward to the next visit and other visits like this.”   “Having patients and their families on site really drives home the importance of our job. It never fails to touch me when I hear them speak. We do great work here. Work that keeps people alive. We sometimes forget.”

Other manufacturers offer tours of their facilities, too. I’ve toured the Bayer plant in Berkeley, and know other families who have seen the Grifols plant in Los Angeles, and the CLS Behring plant in Kankakee, Illinois. Ask your local rep if you can see their plant, and learn how factor is made.

And read the August issue of PEN, coming to your mailbox soon; we review all factor products and manufacturers, and chart out the new products coming in the pipeline.

Thanks to Gail McCarthy, our local Pfizer rep, for this invitation, to the families who took a day off to join us, to the Pfizer staff who made this such a pleasant and educational day and who care enough to meet and learn about our very special community.

Good Book I Just Read
The Doors Unhinged: Jim Morrison’s Legacy Goes on Trial
by John Densmore

Laurie Kelley with Robby Krieger of the Doors


An unflinching account of the 2002 lawsuit by Densmore, former drummer for the 60s band the Doors, against his former bandmates, keyboardist Ray Manzarek (who just passed away in May) and former high school best friend guitarist Robby Krieger. His suit was primarily to stop the use of the name and logo of the Doors by Manzarek and Krieger, who were touring (without Desnmore) as the “Doors of the 21st Century.” He did not seek to stop them from playing or from calling themselves “Of the Doors.” He did not seek money from this lawsuit. Manzarek and Krieger countersued for $40 million, claiming that Densmore vetoed a $15 million commercial with Buick… and then Densmore’s real beef is revealed. Densmore goes to court to preserve the noncommercialsm of the original Doors, particularly frontman and cultural icon Jim Morrison, by not “selling out” to corporate America; and to honor the Doors agreement that all bandmates had equal weight in determining decisions with equal veto power. Indeed, Densmore was backed throughout the trial by the estate of Jim Morrison, and even Morrison’s father, a former rear admiral in the Navy, testified. Densmore further questions the need of Americans, and in particular his bandmates, who are all wealthy, to accumulate millions more at the risk of losing their creative purity. It’s an interesting question; Densmore makes many good points, even though at times he unnecessarily takes uncomfortable jabs at Manzarek in particular. Yet Densmore himself stands to earn a lot by being a former Doors member, and writing these books! It’s a head-scratcher at times, as you wonder from what angle Densmore is coming sometimes, as there are many; his arguments don’t always seem clear or follow logically. It’s a quick read, raises good questions and will generate a lot of discussion. From an insider, I have heard that the book is quite accurate.
For devoted Doors fans, this is a hard book to read, to learn what has become of their legacy. I’m a bit biased as I love the Doors, and appreciate each musician for their talent and dedication, and just met up with Robby Kreiger on Saturday night at the Hard Rock Cafe–he’s a nice guy, by everyone’s account. He wrote my favorite song ever, “Touch Me,” which I admit would have a different meaning and feel entirely if it were used as a commercial for say the iTouch. For anyone in rock and roll, it is a fascinating legal read. Two/five stars.

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