Our Excellent Biologics Safety Record: It’s No Accident

LAST YEAR, 30 domestic and overseas manufacturers distributed some 140 different plasma-derived therapeutics and vaccines for human use to U.S. hospitals, clinics, pharmacies and homecare providers. Thousands of batches and hundreds of millions of doses of vaccines, immunoglobulins, coagulation products, topical hemostasis agents, blood volume expanders and a host of other products were infused, injected or delivered by spray applicator.

Yet, throughout 2009, the Food and Drug Administration (FDA) reported just three product recall actions, which involved an anti-pneumococcal vaccine and a few batches of 2009 H1NI influenza vaccine. None involved any safety risk to patients. And in each instance, the FDA determined that the implicated lots were sufficiently potent, making it unnecessary even to revaccinate any patients.

That extraordinary 2009 safety record was no fluke. During the previous five years, from 2004 through 2008, the FDA reported an average of just three limited biotherapeutics recall actions a year.And, only three of those 15 recalls involved adverse clinical events; all were transient, non-life-threatening allergic reactions.

How can an industry that makes most of its products from human plasma and live viruses supply so many therapies at such volumes with this record of quality and safety?

It Starts with the Raw Material

No products approved for human use are subjected to more regulatory oversight than biologics. And, none receive more FDA scrutiny than those sourced from human or animal blood.

The FDA regulates these products under the authority of not one, but two laws: the Public Health Service Act and — because they also are considered drugs—the Food, Drug and Cosmetics Act. Under these laws, the FDA promulgates explicit rules, which can be found in Title 21 of the Code of Federal Regulations (CFR), that are binding on both the agency and industry.

Conforming to regulations enforced by the FDA’s Center for Biologics Evaluation and Research (CBER), plasma collection operations must strictly follow their own standard operating procedures (SOPs)for donation and subsequent handling, freezing, storage and transportation of the plasma to the manufacturer for “fractionation” into immunoglobulins, coagulation agents, albumin and other therapeutic proteins. These SOPs help to ensure that products are free of contamination by transmissible agents. And, manufacturers incorporate CBER’s “five overlapping layers of blood safety” in the collection of human plasma:

• plasma donor eligibility screening
• plasma testing for communicable diseases
• maintenance of donor deferral registries
• quarantine pending testing/records verification
• investigation and correction of system deficiencies

An important sixth “layer” of safety comes later during the fractionation process itself, when manufacturers employ multiple highly effective viral separation and inactivation methods.

Approving the Plant, and Policing the Process

Yet, even before any new plasma-based therapeutic is approved, CBER must inspect the production plant and review protocols for all process steps. CBER specifically seeks to determine whether the processes are well-validated and if there is sufficient quality assurance documentation in place. If everything complies with its “Current Good Manufacturing Practice” (cGMP) rules, CBER will grant an establishment license to the manufacturer, allowing it to make and distribute that product. Thereafter, CBER conducts plant inspections on a regular basis to assess whether products continue to be manufactured in compliance with applicable regulations.

And, with so many products made at so many facilities and spread across several continents, CBER recognized that the industry also needs to step up and police itself. So, a decade ago, in November 2000, the agency amended its regulations to require manufacturers to report any “biological product deviations” from cGMP standards or unforeseen events that might affect product safety, purity or potency. Once such a “deviation” is reported, the manufacturer must demonstrate that it has corrected the problem.

This strategy of joint FDA-manufacturer accountability has clearly succeeded. And, it has succeeded in other ways as well. With joint technical workshops and formal comments on proposed regulations, for example, manufacturers and the FDA work in collaboration to ensure product safety and integrity.

One More Hurdle: Lot Release Testing

Once product is manufactured, CBER requires manufacturers to perform specific tests to ensure the purity, safety and content of active components for each lot (or batch) of a vaccine, plasma product or other biologic intended for human use. Samples from each lot accompany a release protocol that summarizes its production history and the results of all tests performed on it.

Some of the key lot release specifications for human immunoglobulin products, for example, include:

• physical appearance
• total protein content (g/dL)
• IgG antibody content (%)
• monomer and dimer content (%)
• product sterility (in vitro culture growth medium test)
• pyrogen (in vivo temperature elevation test)

CBER also may run confirmatory tests itself on some lots before allowing them to be released for distribution.

The Last Line of Defense: Post-Marketing Surveillance

Thanks to the layers of regulations, SOPs, inspections and testing, plasma products and vaccines that leave the plant almost invariably conform to their safety, potency and purity standards. But, we all know that a risk-free world remains an unattainable fantasy: There always will be that rare instance when a product somehow falls out of compliance without being detected. And, sadly, there always will be the few unscrupulous individuals who, for illegal gain, improperly tamper with products or attempt to redirect them through the hands of unauthorized or unlicensed parties.

To respond quickly to serious adverse events or therapeutic failures that might reflect an underlying product-related problem, the FDA relies on health professionals to voluntarily report them through its “MedWatch” Adverse Event Reporting System (AERS).

A separate surveillance program, the Vaccine Adverse Event Reporting System (VAERS), accepts reports from providers, manufacturers, patients, parents and guardians about adverse events thought to be associated with licensed vaccines. VAERS fields about 30,000 adverse event reports each year, some 10 percent to 15 percent of which involve permanent disability, hospitalization, life-threatening illness or death.And, most of the time — although not always — the association between the vaccine administration and one of these serious adverse events is entirely coincidental.

However, if its review of these reports does lead the FDA to conclude that certain adverse events are directly related to the vaccine or other biologic, the agency can order that product to be recalled. And, just as important, reporting adverse events can lead to prompt corrective measures to address the product’s manufacturing process, handling, storage and use. And, when suspicions that a product may be counterfeit provide to be valid, criminal investigations also will ensue.

Beyond FDA Regulation: The Industry’s QSEAL Certification Program

To help define applicable FDA regulations and to extend beyond them, the Plasma Protein Therapeutics Association (PPTA) has developed its own standards and voluntary certification program for plasma sourcing and fractionation. Once an independent auditor inspects and reports on how closely a fractionator’s policies, procedures and facilities adhere to its supplemental standards, PPTA makes the decision whether to award its QSEAL certification to that company. QSEAL is perhaps the most visible example of the industry’s shared responsibility with the FDA to ensure product safety and integrity.

Of course, the beneficiaries of this industry self-scrutiny and unceasing FDA regulatory oversight are the patients who trust that every dose they receive contains exactly what they ordered. Nothing more and nothing less.