Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

There were lots of subtle and not-so-subtle messages about industry's failure to comply with basic GMPs brought up during the PDA-FDA joint regulatory conference last month in Washington, DC. FDA speakers made it clear that the most common GMP inspection citations have not changed much in the past decade, suggesting that industry has not yet gotten its act together. Most observations found by inspectors continue to be tied to the quality control unit and overall deficiencies in quality management systems. And as we have learned during the past few months, these types of deficiencies can lead to drug recalls and ultimately, drug shortages, a major public-health concern. 

A few conference participants brought up the notion that "to comply" is to go against human nature. It's much more natural, they suggested, to try and hide a mistake or to rely on one's own opinions about how things ought to be done, as opposed to following a set of rules. It's not so much defiance that is causing quality problems, however, as is a lack of training, they added. For example, if someone in the testing department does not understand why he cannot walk into a sterile room with regular shoes on, why would he make a big deal out of doing so? In many cases, employees just don't understand 

 certain procedures must be followed and what the consequences are for not doing so. One FDA speaker pointed to a small company of 10 employees that was recently found to have not undergone 

So the larger elephant in the conference room was the fact that industry senior management needs to take a more proactive role in understanding and explaining  quality GMPs and risk-based approaches to all employees, at all sites. The patient—rather than the bottom line—must be in the minds and goals of management at all times in order for a sense of ownership and responsibility to trickle down. One audience member even suggested renaming Good Manufacturing Practice to be Good Management Practice. I expect we'll hear more on this topic in the future. 

Articles

Corporate management must be held accountable for quality at all levels.

Is Noncompliance Just Human Nature?

FDA Commissioner Margaret Hamburg and US Assistant Secretary for Health Howard Koh released a statement on Sept. 9, 2011, aimed at a stakeholder meeting held at the US Department of Health and Human Services (HHS) to address the growing problem of drug shortages in the United States. The shortages affect many necessary drugs, including those for cancer, anesthesia, influenza, and other critical conditions.

In 2010, there were 178 drug shortages reported to FDA, 132 of which involved sterile injectable drugs, according the agency’s 

frequently asked questions website for its Drug Shortages program

. So far this year, there has been “an increasing number of shortages, especially those involving older sterile injectable drugs,” according to the site.

“All parties involved in the supply of drugs to Americans have a responsibility to make sure patients have access to the drugs they need,” states an 

The agency intends to release a report in the coming weeks that analyzes the problem and provides recommendations. “One suggestion is a mechanism for manufacturers to report impending supply disruptions and discontinuation of drugs, which could help to curb drug shortages and improve the continuity of the drug supply,” according to the press release.

“Meanwhile, the FDA will continue its efforts to work with manufacturers to ameliorate shortages. For example, FDA already expedites requests to qualify new manufacturing sites, new production lines or new raw-material suppliers to avert drug shortages. HHS remains committed to working with manufacturers, providers, patient advocates, and other stakeholders to help minimize drug shortages, protect patients, and identify solutions to this serious problem,” said the statement.

FDA will hold a public workshop on Sept. 26, 2011, in Silver Spring, Maryland, to further discuss drug shortages and the Center for Drug Evaluation and Research’s approach for addressing them. The causes and effects of drug shortages, as well as possible strategies for preventing or mitigating them, will be discussed.

Drug Shortages Rise, but No Requirement to Report Them

Drug Shortages Encourage Gray-Market Activity

FDA Commissioner Margaret Hamburg and US Assistant Secretary for Health Howard Koh released a statement aimed at a stakeholder meeting being held at the US Department of Health and Human Services to address the growing issue of drug shortages in the United States.

FDA and Department of Health Address Drug Shortages

[originally posted as a blog Sept. 14, 2011]

Today, FDA’s Deputy Commissioner for Global Regulatory Operations and Policy Deborah Autor testified before the US Senate HELP committee regarding the pharmaceutical supply chain and related security issues. She asked for additional FDA authority in several key areas.
  These areas include:

  The authority for FDA to promulgate enforceable standards for a national track and trace system. This system should not be able to be pre-empted by state standards, noted Autor. (During the Q&A, GAO, GPhA, and PhRMA representatives said a simple barcode requirement on every product made overseas may be costly and hard to implement and harmonize.)

The authority for FDA to be able to refuse products from a foreign manufacturer if and when that manufacturer has refused or delayed an inspection (Autor noted that the law is not clear in this area and needs to be clarified. Others suggested sanctions for foreign companies that refuse inspections).

The authority to issue mandatory recalls of drug products. [The agency has this power for medical devices but has only used the power three times according to Senator Michael Enzi (R-WY)]

Autor also requested that Congress take action to legally require that drug manufacturers report to FDA drug shortages, contamination, and cargo thefts.
    In general, Autor called for a level playing field for industry. Right now, there are companies who have good quality systems and supply chain tracking and there are companies who do not, she said. The standards need to be raised to require at least a minimum of quality and GMP standards among all manufacturers. In addition, there should be requirements, as there are in other countries, to prove that a product is “good” before it can enter the US market, versus the current requirement that FDA find something “wrong” with a product to deny its entry, she noted.

    Senator Barbara Mikulsi (D-MD) in particular stressed the urgency of securing the pharmaceutical supply chain, using the heparin incident as an example. “This issue needs to be elevated to a national security, a homeland security, and a criminal level … so that American people know that if they take [a drug], it will be okay.” Autor agreed with the Senator’s viewpoint.

    The hearing was based on the pending PDUFA reauthorization and recent GAO recommendations that FDA be placed on a high-risk watch list of organizations until it more effectively uses its enforceable authorities to make drugs safe for the US market. Senate committee members were concerned about how to handle the fact that 40% of drugs in the US are manufactured outside the country and 80% of APIs are manufactured outside the country, along with growing counterfeits, economically motivated adulteration, cargo thefts, and other supply-chain problems.

    Senator Enzi questioned FDA’s response to GAO recommendations to better inspect foreign facilities and to do so with a risk-based approach (i.e., facilities posing greater risks be inspected first). Enzi also questioned why FDA has not updated its API, quality, GMP, and supplier guides for industry to meet current global challenges.

    Autor acknowledged the gap between FDA’s statute and the state of global manufacturing. She noted the agency’s efforts to increase information-sharing and training, its harmonization efforts, and its updating of standards. “We’re doing all we can to address GAO’s recommendations,” she said. She pointed to FDA’s Pathway to Global Product Safety and Quality, a new strategy released in June 2011.  She also noted partnerships with Europe and Australia as a means to improve the global regulatory landscape by sharing inspection information. FDA cannot do it alone, we need harmonized standards and we need to be able to rely on each other, she said in reference to a global regulatory system.

    HELP Committee Chairman Senator Tom Harkin (D-IA) questioned the agency’s limited resources and ability to conduct necessary foreign inspections and the staffing of FDA’s overseas offices such as that in China. He questioned why inspections overseas are preannounced, which Autor explained is necessary because the agency has to get a VISA to enter a country such as China and also must receive a letter of invitation from a country to inspect. This legal situation does not allow for unannounced inspections as we have in the US and needs to be changed, she said.

    There was a discussion about whether FDA needs legislation or regulations to improve its enforcement. Autor suggested that if Congress is concerned about these issues that it should take a legislative approach and to make the legislation urgent. Senator Enzi responded by asking for a list of specifics to get Congress going.
    Senator Michael Bennet (D-CO) noted that if ever there was a time for a bipartisan approach, this issue of the supply chain is it.
    Senator Al Franken (D-MN) asked whether manufacturers should be held accountable for their suppliers and supply chains to take the burden and cost off FDA. Autor said absolutely and that manufacturers are in the best position to do so—they know their products, their risks, and their supply chain players. But it needs to be clear in the law that they are responsible, she added, again calling for Congressional action.

    The committee concluded by saying that it will be looing at track and trace sytems, inspection requirements (how often and who), FDA authorities, and more.
    Drug shortages, transparency with the public, show factories, and pharmacy burdens were also discussed.

    Autor’s full testimony will be posted to the HELP committee website. Other testimonies came from GAO, PhRMA, GPhA, Rx-360, and the PEW Health Group

Deborah Autor testifies before US Senate HELP committee on requested authorities to improve pharma supply chain.

FDA and Senate Call for Urgent Supply Chain Attention

FDA’s Division of Drug Marketing, Advertising, and Communication (DDMAC) issued a 

 to Pfizer’s vice-president of US Regulatory Affairs regarding its online resources page for Lipitor (atorvastatin calcium) tablets. The letter, which was brought about as part of the agency’s Bad Ad program, cites that the webpage is misleading because it makes representations and/or suggestions about the efficacy of Caduet (amlodipine besylate/atorvastatin calcium) tablets, Chantix (varenicline) tablets, and Norvasc (amlodipine besylate) tablets without communicating risk information associated with the use of these drugs.

The letter reviews the FDA-approved indications and side effects for these products and notes that DDMAC sent Pfizer a letter in 2009 regarding sponsored links on Internet search engines for several of its products, including Caduet and Chantix. Those links were deemed misleading as well and “DDMAC is concerned that Pfizer is continuing to promote its products in a similarly violative manner,” states the current letter.

Promotional materials that include the name of a drug but not its indications are required to disclose risk and other information, states the letter. Otherwise, the materials are considered misleading.

Chantix in particular has a boxed warning, which was omitted in the webpage, and the lack of risk information about all the products noted on the webpage “suggests that these drugs are safer than have been demonstrated,” states the letter.

DDMAC has asked Pfizer to immediately stop disseminating the promotional materials and to submit a response letter to the agency by Sept. 14, 2011.

FDA's Division of Drug Marketing, Advertising, and Communication issued a letter to Pfizer's vice-president of US Regulatory Affairs regarding its online resources page for Lipitor tablets.

FDA Issues Letter to Pfizer Regarding Violative Online Marketing

Excipients used as active ingredients in pharmaceutical products, otherwise known as atypical actives, have received much attention during the past several months. Industry is questioning whether—and why—these unique ingredients need to comply with the International Conference on Harmonization's Q7 guideline on GMPS for active pharmaceutical ingredients (1).

spoke to David R. Schoneker, past chair of the International Pharmaceutical Excipients Council, to gain some insight into the ongoing debate.

A typical actives, defined as excipients that are used as active ingredients in pharmaceutical products, have been around for decades and presumably represent little or no risk to patients. They can be found in many common over-the-counter items such as rubbing alcohol (the atypical active is isopropyl alcohol) and antacids (the atypical active is calcium carbonate). So why all the recent attention over their use?  

Since the International Conference on Harmonization (ICH) finalized its Q7 guideline on GMPs for active pharmaceutical ingredients (APIs) in 2000, actives have received greater scrutiny. Quality-by-design approaches and recent supply-chain security problems have encouraged this in-depth review. Industry thinking is that, even though ICH Q7 is not a legal requirement, excipients used as APIs should adhere to the guideline (1). However, most excipients are not designed to be used as an active and are produced using GMPs aligned with the 2006 International Pharmaceutical Excipients Council–Pharmaceutical Quality Group (IPEC–PQG) Excipient GMP guide (2). Requirements between the two guidelines differ, and there is controversy regarding what should be expected in terms of compliance for atypical actives. 

To understand why this difference exists, it is important to step back and look at the excipient industry in general. The chemicals used as excipients are used in many industries, including chemicals and petrochemicals, food, and plastics. Only a small percentage of all these chemicals used as excipients are found in pharmaceuticals. Excipients that are supplied to the pharmaceutical industry are largely produced and intended for use as inactive ingredients in drug formulations, not as active ingredients. 

There are processing differences, too, explains David R. Schoneker, past chair of IPEC and director of global regulatory affairs at Colorcon. "In general, full GMPs for APIs begin to be applied early in their manufacturing process, whereas GMPs for excipients are applied later in the process, such as during final finishing steps," he says. API makers know from the start that their material is going to be used in a pharmaceutical product. Excipient makers may not have this same knowledge. The degree of documentation and oversight of the manufacturing process also varies between APIs and excipients. "Although the principles and areas of concern are the same, there are additional second checks and oversight (e.g., additional validation) with APIs, and there is a significant cost associated with this," adds Schoneker.  

At present, there are no official FDA GMP regulations that exist specifically for excipients. "They are considered drugs according to the federal Food, Drug, and Cosmetic Act, but that document only says that 'appropriate GMPs must be used,'" explains Schoneker. For this reason, the IPEC–PQG Excipient GMP guide is helpful to excipient makers looking to apply best practices. In fact, IPEC and PQG, with FDA collaboration, are working to get their excipient GMP guide approved as an official ANSI standard by the end of 2011. If this occurs, the document will become the national standard for Excipient GMP in the US, and FDA will be able to use it and reference it officially as the acceptable GMP practice for excipient manufacture during inspections.  

The IPEC–PQG guide and the pending ANSI standard would apply to general pharmaceutical excipients, however, and not to excipients used as actives. And this is where a resolution is needed, says Schoneker.  

Many FDA investigators expect ICH Q7 to be adhered to when excipients are manufactured for use as actives in a drug product, he says. ICH Q7 has been used by FDA as the GMP standard in a number of inspections of excipient manufacturers that were not aware that a pharmaceutical company was using its excipient as an active. In these cases, the excipients manufacturer is often caught off guard. When FDA shows up to do a routine preapproval inspection, it can result in a Warning Letter for noncompliance to ICH Q7 even though the excipient manufacturer may inform FDA that it had no intent for is material to be used as an active by its customers. 

Part of this problem is due to a lack of communication between final dosage-form drug manufacturers and excipient manufacturers—it is often the case that the excipient manufacturer and/or supplier do not know the use of a particular excipient. Industry and regulators are trying to improve this dialogue through various transparency and information-sharing initiatives.  

But the bottom line is that excipient manufacturers and suppliers do not want to have to upgrade their facilities or processes to adhere to ICH Q7 for excipients used as atypical actives, especially when they have little business interest in selling their excipient products for these purposes. The additional controls, documentation, and cost, in most cases, would not be worth their return on investment. As a result, they may turn away from the pharmaceutical industry and this action could lead to a shortage of supply of the atypical actives. This would be a huge problem, says Schoneker, because it could force many drug manufacturers to have to reformulate their products or it could lead to the removal from the marketplace of many commonly used products. 

To address these growing concerns, IPEC has been working with PDA and other industry stakeholders to develop a guideline specifically for atypical actives that would ultimately have FDA buy-in. Some potential solutions, says Schoneker, would involve having regulatory flexibility related to GMP expectations for existing atypical actives that have been used for years without safety problems. For atypical actives used in drug products, use of the IPEC–PQG excipient GMP guide, would be an appropriate GMP to use. There may be situations where additional technical considerations or specifications are required depending on the specific aspects of a particular material and its use. These details would need to be negotiated between the excipient manufacturer and the final drug-product manufacturer based on the material's intended use, he explains. Additional technical considerations and specifications, however, are not a higher level of GMP. The separation of the two definitions needs to be discussed among industry and regulatory authorities.  

"We need to have a resolution that is acceptable to excipient makers, users, and regulators that makes them feel comfortable that appropriate controls are in place and that provides security to makers and users that they are not in a position of liability," says Schoneker. 

IPEC's working group on atypical actives is in the process of working through this subject and will be presenting ideas and discussions at various upcoming industry meetings. For more information, please contact IPEC–Americas at 

Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients

Clarifying GMPs for excipients used as actives.

Atypical Actives Gain Attention

The US Pharmacopeia (USP) continues to expand its collaboration with drug authorities around the world, this time with Brazil’s regulatory agency. USP and the Brazilian National Agency of Sanitary Surveillance (ANVISA) are teaming up to develop joint education activities for professionals involved in formulating and using pharmacopeial monograph standards in Brazil, according to news releases on the 

“The organizations [are] committed to work together in developing joint education activities for professionals involved in formulating and using pharmacopeial monograph standards,” says a USP release. “The agreement acknowledges that both organizations share common goals for improving public health related to quality medicines through education.”

In addition to drug regulation, ANVISA oversees the 

The agency has offices in São Paulo as well as in the United States. Products manufactured in Brazil and sold into the US market must meet USP standards, which are enforceable by FDA.

According to Dr. Dirceu Barbano, director-president of ANVISA, “With Brazil’s continuing emergence as a center for global pharmaceutical manufacturing, cooperative efforts with organizations like USP will help to refine and strengthen our capabilities in ensuring good quality medicines and their ingredients,” he stated in the USP news release [see Brazil’s perspective in a recent 

As part of the educational activities, USP and ANVISA plan to:

Increase awareness of the quality, safety, and efficacy of medicines and foods

Promote cooperation between the organizations to improve the quality of medicines and foods

Improve the exchange of information, including scientific and technological knowledge that may contribute to research and teaching

Facilitate the harmonization of pharmacopeial standards

Establish a basis and mechanism for cooperation between the two parties.

Implementation of the agreement will involve leadership from USP’s facility in São Paulo and its global headquarters.

USP has expanded its international reach in recent years through drug-quality partnerships with other national drug authorities, such as that in Russia. The organization runs a program in collaboration with the US Agency for International Development called Promoting the Quality of Medicines (PQM). The program is aimed at helping to ensure the quality, safety, and efficacy of medicines essential to USAID priority diseases, particularly malaria, HIV/AIDS, and tuberculosis.

Of note, Hellen Berger reports on the Brazilian pharmaceutical industry in PharmTech’s September issue. Also in the upcoming September issue: a debate about USP’s international goals.

USP and the Brazilian National Agency of Sanitary Surveillance are teaming up to develop joint education activities for professionals involved in formulating and using pharmacopeial monograph standards in Brazil.