Five Years Later, Legacy Biologics Still Face ‘Next Heparin’ Risks

Several factors continue to slow efforts to modernize legacy biologics’ compendial monographs against fake ingredients like the ones someone put in heparin in 2008. Hyaluronate, the ‘poster child’ for monograph modernization; New NDAs for pancreatin create new modernization challenges; Heparin maker vertically integrates to prevent adulteration.

Five years after scores of people died because someone slipped fake active ingredient into heparin supplies, compendial test upgrades to protect other legacy biologics from such threats remain mired in the same glacial compendial process that heparin was in before the crisis.

There has been some progress. Post-crisis compendial upgrades are in the third round for heparin. High pressure liquid chromatography assays were proposed to replace animal assays for glucagon and glucagon for injection, and there is a general chapter in the works for insulin.

But many relatively poorly characterized older biologics remain wedded to older, less specific compendial testing methods.

Meanwhile, despite significant legislative and cost hurdles, the strengthening of supply chain controls in response to the heparin crisis has advanced relatively quickly.

FDA and the European Medicines Agency are implementing post-heparin legislation to increase the identification, inspection and auditing of active pharmaceutical ingredient manufacturing facilities, while the International Conference on Harmonization has added its Q11 guideline on development and manufacture of drug substances.

Biologics modernization challenges

In the wake of the heparin incident, the U.S. Pharmacopeia in Rockville, Md., has encountered a combination of factors that make it difficult to modernize biologics compendia.

Tina Morris, USP’s vice president for biologics and biotechnology, recently spoke with “The Gold Sheet” about the challenges facing efforts to modernize monographs for biologics like heparin.

USP has a priority list for modernizing small-molecule monographs, but it’s still working on developing one for large molecules, she noted (Also see "Shortcuts Pursued in Effort to Close Compendial Gaps" - Pink Sheet, 1 Sep, 2011.).

Morris explained that in setting priorities for upgrading biologics monographs, “the challenge is that we’re dealing with a lot of different molecule classes, and a very diverse portfolio. But we have identified some priorities.”

For example, she said, USP’s Biologics and Biotechnology 1 Expert Committee, the one that handles the heparin monograph, has been working to update the pancreatin monograph with the help of a dedicated expert panel.

The committee also is discussing monographs for peptide hormones, as well as other glycosaminoglycans like sodium hyaluronate, which has been described as a “poster child” for monograph modernization.

Morris said biotechnology companies “build a lot of very sophisticated testing into product development.” The testing in the chemistry, manufacturing and controls sections of their investigational new drug and biologics license applications typically reflect the latest analytical approaches, she added.

But the situation is different with older biologics like heparin, hyaluronate and pancreatin.

“Many of the companies that work on legacy products have not, in the past, been asked or forced to update their analytical portfolio,” Morris explained. “For them, I think it requires a much, much more radical change from the way that things have been done in the past. So you’re working with an industry that is not used to constantly upping the analytical game, if you will, and they’re not used to working on things like quality by design.”

She said another factor is that legacy molecules “are very challenging analytically, and if they’re naturally derived, they come with a host of really big analytical challenges, adventitious agent testing, things like that.”

Another challenge is that each molecule has many manufacturers, she said. “You’re dealing with a large group of manufacturers out there that are affected by a [compendial] revision, and if you compare that to a modern biotechnology drug that’s still under patent, there’s one manufacturer or there are very few manufacturers.”

The fewer the manufacturers, the easier it is to change analytical methods. “If you’ve got a big group and you want to be really responsible about the standards development, you have to do round robin testing, big analytical studies, and that takes time.”

Yet another challenge: economics. Legacy biologics tend to be high-volume, low-margin products, and adding expensive analytical methods could impact profit margins. “It’s certainly a different situation financially from some of the very, very high value biotechnology products,” she said.

Finally, there’s the cultural factor. “In the legacy product area, you’re dealing with a very conservative industry that has had products out there for a long time and probably is just a little bit change-averse in general.”

Crisis hastened heparin revision

This combination of factors played into the heparin crisis. Heparin sodium dates back to the mid-1930s and was first approved in 1939 under the Food, Drug and Cosmetic Act, enacted the year before.

USP’s heparin sodium monograph, established in 1950, had gone through several revisions over the years, including the addition of the anti-Factor Xa assay.

After an effort to modernize the monograph by replacing the sheep plasma clotting assay with a chromogenic anti-Factor IIa assay stalled at the proposed stage, USP formed an ad hoc advisory panel in 2006 to give it another try.

Proposed in February 2007, the anti-Factor IIa assay “was ready to move forward to official when the crisis broke,” USP says.

The pharmacopoeia quickly added nuclear magnetic resonance and capillary electrophoresis identification tests FDA laboratories developed during the crisis to protect the market from heparin tainted with the fake API, oversulfated chondroitin sulfate.

The anti-Factor IIa assay replaced the sheep plasma clotting assay in a Phase 2 revision that came soon after (Also see "USP Adds Heparin, Glycerin Tests While FDA, Army Labs Try New Test Methods" - Pink Sheet, 1 Feb, 2009.).

A “poster child” for modernization

A frank discussion of a proposed sodium hyaluronate monograph at a recent meeting of USP’s Biologics and Biotechnology 1 Expert Committee illustrates some of the difficulties facing modernization efforts.

One USP staff member suggested that the product “probably qualifies as the ‘poster child’ for modernization.”

FDA’s center for devices first approved sodium hyaluronate as a viscoelastic surgical aid in 1986. The substance, which appears naturally in connective tissue, is injected to ease arthritis knee pain, and in eye surgery.

Participants in the March 2012 meeting agreed that sodium hyaluronate is widely used, typically involving large doses to knee joints or eyes, which suggests a significant risk that someone could commercially benefit from adulterating it, and that such adulteration, if it occurred, could cause real harm.

There is as yet no USP monograph for this product, but one of its manufacturers has proposed a monograph, which was the focus of the discussion.

The proposal did not wow the committee. A USP staff member described it like this: “The analytical procedure is complex. There’s a lot of wet chemistry involved. It’s all done in test tubes.” He suggested looking into less people-intensive, less error-prone approaches such as using 96-well plates.

One participant suggested that the method “actually resembles the old heparin monograph a lot.” Another agreed, highlighting “the antiquity of the methods.”

Asked why “these old-school methods” were proposed, the USP official replied that they’re from the sponsor’s own release tests.

There ensued a discussion about how to engage the sponsor and its competitors in a process of upgrading to more modern, instrumented methods for sodium hyaluronate.

One participant reminded the group that “as you recall even from heparin, unless there is an issue, a public health issue, it’s very difficult for USP to go back to manufacturers and suggest changes.”

Even so, another participant suggested that if no sponsors would support modernization, USP’s laboratory could step in to develop modern methods, for example high pressure liquid chromatography methods that could identify hyaluronate in a very specific way.

However, one participant cautioned that USP would need to alert the manufacturers first, “because if you go ahead and put in a 500 Megahertz NMR [nuclear magnetic resonance] method, they will have a cat fit.”

“As they did with heparin,” a USP participant interjected. “Even with heparin, with 80 people dying, we got strong pushback for the NMR method, strong pushback. I can’t even imagine what kind of pushback you’re going to get if you put an NMR method in.”

The group went on to discuss how it would modernize the monograph without triggering such a conflict, perhaps as one participant suggested, by working to find a middle ground between NMR “and what we have now.”

Morris later told “The Gold Sheet” that, “based on the recent heparin experience, the expert committee actually turned that proposal down because the tests that were proposed were not modern tests.”

She added that USP is “looping back” with hyaluronate manufacturers on coming up with a truly modern monograph.

New methods, new challenges

In the case of pancreatin, which replaces three enzymes the pancreas normally makes, recent FDA approvals have changed the dynamic, but haven’t ensured modernization of the monograph. Pancreatin remains, as USP’s Tina Morris said, “a very challenging molecule category.”

Fouad Atouf, USP’s director for biologics and biotechnology, noted that like most USP monographs for enzymes, the pancreatin monograph needs an identity test and could benefit from more modern assays.

Pancreatin enzyme preparations predate the FD&C Act and for many years, all but one approved in 1996 were marketed without new drug applications. In a regulatory process that dragged on for a couple of decades, FDA decided to allow only approved versions on the market, the agency explained in April 2006 guidance. FDA has since approved at least four pancreatin products, Atouf said.

The FDA approvals have created new possibilities – and new challenges – for the monograph modernization process, Morris said.

Manufacturers had to create or significantly update their chemistry, manufacturing and controls sections, “which means they are forced to modernize their tests to be compliant.”

However, she said this means the manufacturers have methods they’d rather keep to themselves, noting that the biotech sector generally views its tests and assays as part of the intellectual property that define its products. “There are elements of some of the tests and some of the assays that manufacturers are not that easily willing to share.”

Atouf noted that the expert panel is putting key information about assay components such as acacia and olive oil into a general chapter, as well as general information about preventing viral transmission, as the specifics are either patented or not publicly available.

There is another complication, Atouf said. The panel must choose a chromatographic method for the identity test. The manufacturers use different processes to make pancreatin API, and have paired those processes with different chromatographic methods. Each method has its plusses and minuses.

The manufacturers proposed five alternatives. USP has narrowed the list to three, and has launched a round robin study in which 10 labs test each manufacturer’s API with all three methods. The goal, he said, is to see how robust the methods are and whether they could also address other aspects of quality such as stability or purity.

Morris said pancreatin poses “a problem that’s very similar, in terms of the complexity and the different manufacturing processes, to what we encountered in heparin, because the unfractionated heparin manufacturers all have different processes. They source their material from different raw material suppliers, and if you have a very complex, naturally derived product that’s made by different processes and different manufacturers, it’s much more difficult to determine a procedure and acceptance criteria that will work for the entire industry.”

It is important, for example, to avoid choosing a method that excludes some manufacturers with “lockout specifications,” she said.

Supply chain complexities persist

An Aug. 14-15 USP workshop on heparin characterization explored not only the post-crisis evolution of the heparin compendia, but also efforts to address underlying supply chain issues.

The heparin crisis not only rendered moot the debate over whether to invest in expensive testing, it also exposed the need for an even more challenging and costly initiative to control the supply chain.

“It’s very difficult to trace the material back to the slaughterhouses,” said Ali Al-Hakim of the Office of New Drug Quality Assessment in FDA’s center for drugs.

He said each lot of crude heparin is actually a combination of five or six lots. Each of those came from five or 10 lots of mucosa, which in turn came from 20 or 30 farms, and thousands of pigs.

“If you have one of these lots contaminated, and it ended up in the crude, it’s highly unlikely that you can trace that contamination to that slaughterhouse, or to the farm or to that pig,” he said. “It is very difficult actually to trace the material, and we discovered that during our investigation when the contamination took place.”

An integrated solution

One company based in China, where most heparin is sourced, has taken a new approach to crude heparin management.

Changzhou Qianhong Bio-Pharma Co. Ltd., located in the Xinbei District of China’s Changzhou Province, was established in 1971, has manufactured heparin sodium since 1991, and makes other mucopolysaccarides and enzymes, including chondroitin sulfate and pancreatin.

Xiaoxia Wang told the USP heparin workshop that the company decided to extend GMP controls into its heparin supply chain. But to do this, the company came to realize it would have to also extend management control into the supply chain.

Qianhong achieved this objective by building a new crude plant and putting a joint venture in charge of it. The company formed the joint venture with Yuron Group, the world’s largest pig slaughtering company, to manage the crude heparin manufacturing process consistent with GMP requirements.

The joint venture created to run this operation, called Runhong, “combines Quianhong’s rich GMP management experience and leading heparin manufacturing techniques with Yuron’s scaled raw material supplying,” Wang said.

Wang outlined several critical points for upgrading to GMP management of crude heparin.

• Personnel: “The people in traditional mode, traditional crude heparin manufacturers, have no experience in pharmaceutical industry, so they don’t have a clear idea of good manufacturing practices and so we need to establish a professional management team.”
• QA/QC system: “We need to establish a quality system to manage the crude heparin production activities.”
• Facilities: “We need to install necessary and suitable equipment.”
• Obtaining materials: “All starting materials, in heparin’s case, intestines, must be traceable from the root.”
• Production: “We need to establish SOPs to instruct our activities in the production and all activities should be recorded.”