After reviewing its documentation, the company concluded that routine preventive maintenance and requalification of manufacturing equipment at the site was overdue. Ben Venue suspended manufacturing so that it could assess the entire site and take appropriate corrective actions to ensure the safety of its products. The suspension will affect Johnson & Johnson, which markets Doxil, as well as Pfizer, Hospira, and Teva.

Last month, President Obama ordered FDA to take various steps intended to prevent and reduce drug shortages. The agency will require advance notice from manufacturers likely to face manufacturing disruptions, and it will expedite reviews of new drug suppliers, production sites, and manufacturing changes.

These steps, while helpful, do not address an important factor that contributes to drug shortages: manufacturing deficiencies. Even before Ben Venue conducted its own review, FDA found 48 quality concerns during an inspection of the Bedford site in May 2011. FDA likely needs a larger pool of inspectors to oversee drug manufacturing sites more thoroughly. But the government’s current desire for austerity will probably preclude the budget increase that would make hiring possible.

Maybe FDA should prioritize manufacturing sites for inspection if they are among a few that produce a medically necessary drug such as Doxil. Greater attention to crucial sites could identify problems earlier and, ideally, resolve them without disrupting drug supply.

Alleviating API inspection fatigue

The first pilot involved the EMA, the national regulatory agencies of several EU member states, the FDA and Australia’s Therapeutic Goods Administration (TGA), and concerned joint GMP inspections of API manufacturers. Such inspections have been a hot topic in the industry for some time because they offer the two-fold benefit of increasing the total number of sites inspected and reducing duplicate inspections for manufacturers. According to the final report on the programme, participants shared their surveillance lists and identified 97 sites common to all three regions, resulting in the exchange of nearly 100 inspection reports and 9 joint inspections. The pilot ran from December 2008 until December 2010 and, according to the report, collaboration in this area will continue and expand—initially to other European authorities.

“The increased cooperation established as a result of the pilot programme increased information sharing between the regulators concerned and facilitates work sharing,” explained the final report on the programme. “It also promoted more efficient use of international inspectional resources combined with wider global inspectional coverage to the benefit of public health and patients worldwide.”

The FDA also touted the success of the initiative in a press statement; for instance, the FDA prohibited imports into the US of a firm’s products based on the negative findings from a European inspection. “The information-sharing and collaborative inspections were important milestones in establishing a sense of mutual trust and common purpose among the drug regulatory agencies involved,” said the FDA in its statement.

Improving GCP

The second pilot involved the EMA and the FDA, and was launched in September 2009 with the objective of sharing inspections information and GCP-related documents, and conducting joint inspections. As with the above pilot, the programme has been very productive. The agencies exchanged more than 250 documents relating to 54 different medicines and organised 13 joint inspections.

The final report said: “A considerable amount of information has been exchanged, and this communication has facilitated improvements in the agencies’ inspection coverage and decision-making processes. The thirteen collaborative inspections conducted under this initiative have contributed greatly to each agency’s understanding of the other’s inspection procedures; they have also led to the identification of potential improvements to these procedures.”

The agencies have said that the initiative will continue and that they will incorporate the lessons learned during the pilot. In a statement, the EMA said that the pilot “demonstrates how the agencies can work together to improve the protection of participants in clinical trials and better ensure the integrity of data submitted as the basis for drug approvals.”

Working out the bumps

But it’s not all going to be smooth sailing from now on. The collaboration is, of course, still in its early days and there are some bugbears that need to be worked out. For example, during the API inspection pilot, particularly in 2009, the report notes that a number of duplicate inspections occurred due to issues related to the ‘Master List’ of API sites, such as out-of-date information. Tools that enable the real-time sharing of data, however, may be able to assist in this area. Another challenge identified was the organisation of joint inspections; several inspections were cancelled because of the absence of effective advance planning and logistical issues. As a recommendation, the reports said that the planning of joint inspections should commence as early as possible.

Overall, the reactions from the agencies involved has been positive, with the FDA describing the pilots in a press statement as “important stepping stones toward further global regulatory collaboration”.

Moving forward, however, caution has been expressed about opening the project wider at this early point because of the added complexity. For now, the collaboration will continue in the existing format and will be extended to all the member states of the European Economic Area. As the bumps in the road are gradually smoothed, however, perhaps there will be input from additional parties. The report said: “Nevertheless, it is recognised that extending the programme to more comparable regulatory authorities and possibly the World Health Organisation would certainly need to be considered as a long-term goal, as an efficient worldwide programme of inspections of APIs would be a notable benefit for public health globally.”

The final reports can be downloaded from either the EMA or FDA websites. If you’re looking for some extra reading to get you through Friday, then you can also have a look at these related PharmTech articles:

FDA, EMA, say future inspections likely

Joint API inspections on the rise

But when Committee Chair Representative Darrell Issa (R-CA) recently visited Maridalia Torres, FDA’s Puerto Rico district director, he learned that neither she nor her staff had visited the McNeil facilities since the time of the hearings. What’s more, Torres had not evaluated McNeil’s corrective actions, but had relied on a third-party compliance officer—hired by McNeil—for information. In a letter to FDA Commissioner Margaret Hamburg, Rep. Issa asked whether FDA had taken any disciplinary actions against its Puerto Rico employees.

Last week, Senators Charles Grassley (R-IA) and Max Baucus (D-MT) expressed concerns about the way FDA oversees the citizen-petition process. As the agency was considering the approval of generic alternatives to Sanofi’s Lovenox blood thinner, it reviewed letters from a professor and two medical groups requesting that approval be delayed. At Congress’s request, Sanofi produced documents revealing that it had encouraged the groups to write to FDA. The company paid the two groups more than two million dollars each, and paid the doctor more than $200,000. None of these three parties revealed their financial relationship with Sanofi to FDA in their letters. And FDA apparently did not ask.

In their letter, the senators warned that abuse of the citizen-petition process could delay patient access to “potentially affordable, safe, and effective generic alternatives.” The lawmakers asked what steps FDA had taken to ensure that the process was transparent.

No government agency is perfect, and FDA does suffer from a chronic shortage of resources. But if FDA is at fault in these two incidents, it is because of a lack of diligence rather than a lack of funds. Patients, whose lives are at stake, need the agency’s protection. I hope FDA rises to the challenge of Congress’s tough questions.

Then, last week, the other shoe dropped. FDA and J&J signed a consent decree of permanent injunction that prevents the company from manufacturing or shipping drugs from its Fort Washington facility until it complies with current good manufacturing practice requirements. J&J had closed that facility in April 2010 and submitted a Comprehensive Action Plan to FDA in July 2010 to improve quality systems at its US manufacturing facilities. Subsequent recalls seemed to indicate that the company’s measures were insufficient, however.

J&J’s problems are not limited to Fort Washington—from 2009 to 2010, FDA inspectors found violations of the Federal Food, Drug, and Cosmetic Act at the company’s Las Piedras, Puerto Rico, and Lancaster, Pennsylvania, facilities. The consent decree requires J&J to adhere to a strict timetable to bring these sites into compliance.

Until I read news of the consent decree, I thought that the only fallout from the company’s manufacturing violations would be CEO Bill Weldon’s 3% raise. In fairness, I should mention that his bonus was cut to $1.97 million, but I should also mention that his bonus is still larger than his salary.

The consent decree reassures me that FDA takes J&J’s violations seriously, and I’m more optimistic that the company will get its house in order now that it faces focused government scrutiny. Our health is too important for FDA to tolerate anything less than diligence on the part of any manufacturer. If nothing else, J&J should be worried about healing the black eye that it has given itself. If the company follows the advice of its independent investigator, J&J may be able to make the improvements needed to regain FDA’s approval and customers’ trust.

Last Wednesday, an attorney filed a lawsuit on behalf of death-row inmates in California, Arizona, and Tennessee, asking a judge to block imports of sodium thiopental. The suit alleged that FDA knowingly allowed these states to import the drug from manufacturers that the agency had not approved. Furthermore, the lawsuit alleged that FDA neglected its duty to inspect shipments of the drug.

The focus on the drug manufacturer reminds me of FDA’s poor record of conducting overseas inspections. A September 2010 report from the Government Accountability Office (GAO) observed that the agency had inspected only 11% of foreign drug manufacturers in 2009. Furthermore, FDA failed to follow GAO’s recommendation that it inspect the sites that posed the greatest risk to public health.

Nebraska, whose inmates are not parties to the lawsuit, purchased sodium thiopental from an Indian supplier after Hospira ceased producing it. Although FDA has an office in India, it is not equipped to do on-the-ground oversight. Nebraska’s supplier is thus not likely to have been inspected.

For FDA to anticipate and mitigate drug shortages, it requires a solid and effective way of guaranteeing the safety of imported drugs. Unfortunately, the new federal lawsuit raises difficult questions about how well the chronically understaffed and underfunded agency can perform this task.

Not everyone thinks so. Margaret Hamburg, commissioner of the US Food and Drug Administration, told the Reuters Health Summit last week that lawmakers should think carefully before cutting taxpayer funding for her agency. “It should be recognized if we can’t do our job and do it well there isn’t any other entity that will backstop behind us,” said Hamburg.

Indeed, the agency’s “responsibilities outstrip our resources,” according to the commissioner. Despite budget increases, FDA struggles to perform its growing list of duties, which now includes regulating tobacco.

Hamburg is not alone in her assessment. Budgetary constraints have led FDA to use a risk methodology to target pharmaceutical manufacturing sites for inspection, but this approach is less than rigorous, according to a paper by Warren Adis, associate professor of information sciences at Iona College in New Rochelle, New York. “By failing to specify quality-assurance violations, the FDA is not providing the necessary oversight and guidance to the pharmaceutical manufacturing industry,” said Adis.

And FDA’s response to the increase in internationally outsourced drug manufacturing has not been strong enough, Hamburg acknowledged at the summit. She may have been thinking of the US Government Accountability Office’s recent report, which urged the agency to inspect more foreign manufacturing sites. In fiscal year 2009, FDA inspected only 11% of sites on its list of foreign establishments, according to the report. One of the report’s disturbing findings is that the agency may never have inspected about 64% of the foreign establishments in its inventory for 2009.

If we accept the premises that reducing the deficit should be an urgent priority and that we must cut spending do it, I don’t think that FDA’s funding should feel Congress’s budgetary blade. The public record contains ample evidence that the agency, which is struggling valiantly, is falling short of fulfilling its goals. Hamburg is right—no person or group stands ready to fill FDA’s shoes should the agency falter. Reducing taxpayer funding for the agency would raise citizens’ risk of exposure to tainted, subpotent, or superpotent drugs.

Public health seems to demand more money for the agency, not less. If it wants to reduce the deficit, Congress should find and eliminate waste from the budget. If boosting FDA’s funding is not politically feasible, Congress should at least leave it intact.

Many legislators and citizens at large believe that FDA would be better able to protect public health if the agency had more muscle. Last Tuesday, Senator Michael Bennet (D-CO) introduced the Drug Safety and Accountability Act of 2010, which would give the agency valuable tools. The bill would grant FDA the authority to assess civil penalties for violations of the Food, Drug, and Cosmetic Act and to subpoena documents and witnesses. In a section that reflects J&J’s problems, the bill also would require FDA to consider over-the-counter drugs as risky as prescription drugs for the purposes of manufacturing-site inspections. These clauses would give the agency more teeth and likely influence drugmakers’ operations as well.

Bennet’s bill follows hot on the heels of H.R. 5740, which Representative Edolphus Towns (D-NY) introduced in July. Towns’s bill would enable FDA to order recalls of drugs it suspects are adulterated or misbranded and would pose threats to patients’ health. I believe that the agency should have had this authority long ago. We may trust many pharmaceutical companies to issue voluntary recalls when they accidentally create substandard products, but FDA cannot protect us from careless or unscrupulous behavior without the ability to order recalls.

Now, it’s all well and good to demand more from FDA, but the agency needs personnel and resources to perform the tasks Congress gives it. The Government Accountability Office and the Institute of Medicine have concluded that FDA faces serious funding deficits that prevent it from fulfilling its mandate. That’s why I’m glad that Representative Henry Waxman (D-CA) and Senator Tom Harkin (D-IA), among other lawmakers, have asked Kathleen Sebelius, secretary of the US Department of Health and Human Services (HHS), to tell Congress what FDA requires to protect American consumers. The Congressmen want to be sure that HHS’s budget request will enable them to allocate sufficient funds to FDA in fiscal year 2012.

We should cheer legislators’ efforts to strengthen FDA’s regulatory abilities. But we also should urge them to give the agency the resources it needs. Secretary Sebelius is in the best position to ensure that FDA can protect us from problems such as the J&J recalls. If she assesses the agency’s needs well enough, she might even help FDA to prevent similar problems in the future.

The inspection report in question contains disturbing observations about J&J’s Lancaster, Pennsylvania, facility, which manufactures over-the-counter products such as Pepcid and Mylanta. If the inspectors’ observations are to be believed, plant managers have been taking a laissez faire approach to the facility’s manufacturing operations. For example, inspectors noted that the plant’s instructions for cleaning and maintaining equipment omitted crucial details about the materials and methods required. Nor did the instructions explain how to disassemble and reassemble equipment to ensure proper cleaning. Inspectors also claimed that the plant’s equipment was not inspected routinely according to written procedures.

This state of affairs opens the door to malfunctions, and FDA officials apparently had a chance to witness several of them. During one packaging operation, a capper machine crashed, a cooling loop failed, and operators observed leaky bottles of product. Yet inspectors said that staff did not conduct quality reviews of products that had been manufactured during equipment failures.

Inspectors did not give the plant’s analytical-testing operations high marks, either. FDA officials said the plant’s laboratory controls did not establish scientifically sound test procedures to ensure that products meet standards of identity, strength, purity, and quality. Inspectors observed as analysts strayed from written test procedures without justification. And when employees took samples of drug products to determine their conformance with specifications, they did not properly identify the samples, according to FDA.

The well-publicized quality problems at its Fort Washington, Pennsylvania, plant apparently haven’t spurred J&J to confirm that its other US manufacturing operations are up to snuff. But the new problems in Lancaster also affect Merck & Co. (Whitehouse Station, NJ), which operates the plant as a joint venture with J&J. I’m sure that Merck does not want its reputation to suffer by association with J&J. If it hasn’t already, Merck will probably lean on its partner to help improve the Lancaster facility. It might take this extra pressure to get J&J to seek and address systemic problems at its manufacturing operations. In the meantime, the public will eye both companies with suspicion.

Considered as a single event, the discovery of particulates in a small percentage of therapies produced at the Allston Landing facility might be seen as a normal occurrence. But this episode continues a troubling trend. During the fall of 2008, FDA inspectors found “significant deviations from current good manufacturing practice” at the plant, including the “failure to establish and follow written procedures designed to prevent microbiological contamination of drug products purporting to be sterile.”

The consequences of this failure were illustrated in June 2009, when Genzyme discovered a virus in the plant’s production equipment. Although the virus strain was not shown to cause human infection, Genzyme temporarily halted production at Allston Landing to sanitize the facility.

In this context, Friday’s announcements raise legitimate questions about whether Genzyme is taking sufficient measures to ensure the sterility of products filled at Allston Landing. I think that FDA and the company should begin investigating whether systemic problems are affecting the plant’s operations.

The new contamination also highlights the need for FDA-approved alternatives to the medicines produced at the facility. As things stand now, a prolonged halt in production at Allston Landing could seriously affect the quality of life of thousands of people. Branded or generic competition for Cerezyme and Fabrazyme, for example, would benefit patients.

Before this program, according to the agency, some firms submitted multiple and delayed written responses to Form 483 observations, sometimes over many months. Because FDA reviewed all of these responses before making a decision on whether to issue a warning letter, the process delayed enforcement  and compliance. Now, however, FDA “will not ordinarily delay the issuance of a warning letter in order to review a response to an FDA 483 that is received more than 15 business days after the FDA 483 was issued,” according to an announcement in the Federal Register.

If a response to a Form 483 is received after 15 business days, FDA says it does not plan to “routinely include a response on the apparent adequacy of the firm’s corrective actions in the warning letter.” Instead the agency “plans to evaluate the response along with any other written material provided as a the direct reponse tot he warning letter.” FDA maintains the discretion to issue a warning letter regardless of whether any responses are received.

The program appears to apply the 15-day limit regardless of the number of observations on the Form 483. One hopes this program will help add a greater level of urgency, especially in situations that apparently have not been taken seriously until a warning letter has been issued. I do not want to think some firms may have deliberately delayed compliance by submitting their responses weeks apart, but I can see how the assumption can be made. On the other hand, investigating the cause of some observations and developing a corrective action can be a time-consuming process such that delayed and multiple responses are not uncommon. One hopes, then, this program will be a good first step toward achieving the tough, no-nonsense enforcement the agency needs without also overburdening the industry.