May 2021

Remembering Our Veterans

Today is Memorial Day in the US, when we remember those who gave their lives in service of their country. I had an uncle, Jim Morrow, who died in Vietnam, on October 15, 1967. His name is inscribed on the Vietnam Memorial wall in Washington DC. Those we remember are those who willingly joined the service as career veterans, or were called to active service in a time of war.

I often think of our bleeding disorder community on Memorial Day. We were at war at one time, from the late 1970s through the 1980s, fighting the scourge of HIV. My son with hemophilia was born in 1987, at the height of the HIV battle. The Ray brothers had just been bombed out of their home in Florida. Our “soldiers” were gathering for a battle against pharma and the US government, to hold them accountable for the contamination of our nation’s blood supply. It was a scary time, especially for a new parent. I attended my first NHF meeting in 1992, and witnessed so much hostility and anger, directed at the displays by pharma, and at each other. Some of our community members were taking a legal approach, hoping for compensation through negotiation; others wanted a more militant approach to solving the accountability problem. So many had died. So many.

I was on the “other” side; my baby had escaped the dreaded HIV infection by only a year or two. When I met these leaders and soldiers in the community, I was struck by their dedication, knowledge and courage. Some were dying already, but fought the good fight to win compensation for all. That would be our only freedom. They were victims of this insidious infection, but became soldiers to defend us, the ones who barely escaped. Their efforts ensured a safer future for all.

Many of those soldiers have died now, but I still remember them. I feel honored to have known them. And I always appreciate how by fate, my child escaped their fate by mere months. I keep photos of some of them on a shelf at home, and have for the past 20 years. Names like Michael Davon and Tom Fahey, co-founders of the Committee of Ten Thousand (COTT); Dave Madeiros, a visionary leader who sought to provide funds to the community by owning a specialty pharmacy—his insights into insurance changes and prophecy about managed care and restrictions all came true.

And some photos are of patients who died, who inspire me all the time. It’s important we remember them all, and carry on their legacy. We are of a new generation now, and our community may be forgetting these veterans.

How can you get to know them and remember them? Read And the Band Played On (also an HBO movie). Watch the movie “Bad Blood: A Cautionary Tale.” Buy the book Dying in Vein. If you have hemophilia, or a child with it, knowing your community history is every bit as important as knowing American history this Memorial Day.

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.

Factor Products: Gen H… for Hemophilia

Do you use a recombinant factor product? Do you know how it’s made?

Recombinant products are not produced from human blood plasma. They are produced in large stainless steel tanks, called bioreactors, which contain trillions of cells. Into each of these cells, a gene for human factor has been inserted, or “recombined”—the origin of the name recombinant. These genes produce human factor and release it into the culture medium—a nutritious liquid that keeps the animal (or host) cells alive and growing. Although the source material is not blood, some recombinant products contain extraneous human or animal proteins introduced during the production process or added to the final product.

To distinguish between the various production processes, recombinant products are classified according to generation. Generation refers not only to when the products were first developed and commercially available, but also to the presence of animal or human proteins used in the production process or the final product.

First-generation recombinant products, introduced in 1992, use human or animal proteins in the growth medium. These products also contain human albumin added at the final production stage to help stabilize and bulk up the product.

Second-generation recombinant products contain no human albumin added to the final product, but do use human or animal proteins in the growth medium.

Third-generation recombinant products, first available in 2003, contain no human or animal proteins in the growth medium or added to the final product. They have the lowest risk of transmitting viruses.

And while MASAC (NHF’s Medical and Scientific Committee) has not yet confirmed the nomenclature of fourth generation, Octapharma and Sanofi Genzyme each created a recombinant factor product that is created from a human cell line, not animal. The two companies are calling their products, Nuwiq® (Octapharma) and Eloctate (Sanofi Genzyme) fourth generation.

If you are using recombinant product, what generation is your factor? Download our Factor Comparison Chart and find out!

Factor Products: Purity vs. Safety

Parents and patients often wonder about the safety of their factor product. Our community suffered terrible losses from contamination of the nation’s blood supply in the 1970s and 80s, so safety is paramount for us. But we often confuse purity and safety when describing factor concentrates. Purity and safety often go hand-in-hand, but in a medical context they have very specific meanings.

Purity: a measure of the presence of other proteins, sometimes including other clotting factors, in addition to the specific factor supplied in the concentrate

Safety: the removal or inactivation of potentially harmful substances, including blood-borne viruses, from factor concentrate

So purity refers to how much of your factor concentrate contains just factor, with no other proteins. Safety refers to reducing the risk of viral transmission.

Purity is measured by specific activity, the ratio of the desired clotting factor protein to the total protein in the concentrate, minus any added albumin (a blood plasma protein).

How is factor purified? That is, how are extraneous proteins removed from factor? By a manufacturing process called chromatography. In simple terms, chromatography involves passing a mixture containing factor through a column (like a glass tube). The column normally contains small beads coated with a substance that attracts the factor and removes it from the mixture. The column is then flushed out to release the factor, resulting in a final mixture that is thousands of times higher in purity and more concentrated than the original mixture.

Please don’t be misled by the term intermediate! These products are still of high purity, although not as high as the ultrapure or monoclonal ones. And note that the various purity levels do not mean there is any less quality control or consistency in manufacturing. Recombinant products are not produced from human blood plasma. They are produced in large stainless steel tanks, called bioreactors, which contain trillions of cells. Into each of these cells, a gene for human factor has been inserted, or “recombined”—the origin of the name recombinant. These genes produce human factor and release it into the culture medium—a nutritious liquid that keeps the

animal (or host) cells alive and growing. Although the source material is not blood, some recombinant products contain extraneous human or animal proteins introduced during the production process or added to the final product.

Next week: What do different generations mean?

Excerpted from Raising a Child with Hemophilia by Laureen A. Kelley.

Types of Factor Concentrate

Last week we shared new about Sevenfact, a commercial blood clotting recombinant product made from transgenic rabbits. But that made me think: maybe we should step back and review what types of factor products there are to begin with.

There are different kinds of factor concentrates, all with distinct brand names and made by different companies, but all blood-clotting factor concentrates are classified as one of two types:

Plasma derived • Recombinant

The major difference between the two types is the origin of the factor, called the source material.

• Plasma-derived factor originates from human blood plasma.

  • Recombinant factor originates from genetically engineered mammalian cells containing the human gene for factor (not from human blood).

You might think that recombinant products have an advantage because they don’t come from human blood, but some still contain extraneous (unwanted) proteins—human and even animal. To understand the differences among products, you first need to know how various factor products are manufactured.

Plasma-derived factor concentrates are categorized by their degree of purity. Recombinant factor concentrates are categorized by how they are produced. Different—although very similar—manufacturing processes can create products with slight molecular differences in the factor protein and with varying degrees of extraneous proteins in the final product. Here are classifications of factor products, based on varying degrees of purity or differing manufacturing processes:

Plasma derived

• intermediate purity • high purity • ultrapure (monoclonal)

Recombinant

• first generation • second generation • third generation • fourth generation

Several recombinant factor products also have a prolonged half-life, allowing you to infuse less frequently. The first of these new products was introduced in 2014.

Why are there so many kinds of manufacturing processes? Why not just use one method to produce factor? In some cases, it’s partly a legal matter: if manufacturer A creates an effective way to produce factor, then A usually patents the process. No one else can use it. Manufacturer B will need to find another way! So manufacturers have developed a variety of slightly differing processes to produce factor.

It’s also a matter of purity and safety. Different products use differing source material and require specific types of manufacturing methods to ensure safety. Due to varying production methods and the type of factor, the relative purity of the final products varies. Purity and safety are two terms you must understand to know which brand of factor to choose, because not all factor concentrates are created equal.

Do you know the difference between purity and safety? It’s easy to confuse them. We’ll review them next week!

Excerpted from Raising a Child with Hemophilia, Laureen A. Kelley 2016

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