Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

In July 2009, the US Food and Drug Administration issued a draft guidance for industry titled, 

Incorporation of Physical Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting

. The document was issued in response to the agency's 2004 Counterfeit Drug Task Force Report, which called for guidance to facilitate the use of authentication technologies such as physical chemical identifiers (PCID).  

"Although we have been working individually with manufacturers who have been using these technologies, we needed to get experience with these new and emerging technologies before we could provide appropriate draft guidance for industry," an FDA press officer told 

The draft document discusses design considerations for incorporating PCIDs into solid oral dosage forms and information about related documentation that industry should include in new drug and abbreviated new drug applications or in postapproval materials. The document also addresses concerns regarding toxicology and the use of PCIDs in product packaging and labeling.   

Manufacturers use PCIDs by including a trace amount of an inactive ingredient within an existing section of a dosage form. The inactive ingredient, explains the draft guidance, contains a unique physical-chemical characteristic that can be detected and authenticated with holography, fluorescence, or other techniques. Some examples of PCIDs include inks, pigments, flavors, and molecular taggants. Most PCIDs are already used as food additives, colorants, or excipients with established safety profiles. They can help thwart counterfeiting, which has been on the rise globally. 

According to the FDA press officer, the agency has no plan to create a specific list of PCID products. The agency does, however, recommend using already approved direct food additives such as those listed in the Generally Recognized as Safe (GRAS) notification program or in the agency's Inactive Ingredient Guide (IIG) and using them at the lowest specified levels to avoid adverse reactions. The draft guidance also points out that applicants may revise the labeling or packaging of their product to indicate the incorporation of a PCID and any potential toxicological concerns . 

More than 20 comments on the draft guidance were submitted to FDA by industry, standard-setting organizations, and academia last fall. The Pharmaceutical Research and Manufacturers of America (PhRMA) specifically recommended that FDA clarify in final guidance whether the use of PCIDs is mandatory or voluntary. In its comments, PhRMA questioned whether food-grade PCIDs would be robust enough as an anticounterfeiting measure and suggested that manufacturers use a GRAS or IIG material as a PCID. The association also suggested extending the guidance beyond solid oral dosage forms. Finally, PhRMA noted that FDA should clarify the role of pharmacists and healthcare providers with regard to PCIDs. Portions of the draft guidance, for instance, could be interpreted to mean that these practitioners need to confirm PCID presence before dispensing a product to a patient, said PhRMA in its comments. Practitioners could not perform such a test without specialized detection tools. 

The Biotechnology Industry Organization (BIO) submitted comments as well. The organization seems to favor the use of other less-invasive authentication technologies and anticounterfeiting tools. Although PCIDs are useful in certain small-molecule products, said BIO in its comments, other technologies may "have less direct impact on the safety or efficacy of the product" and may be better suited to liquids and other types of products. Overall, the organization said it hopes other anticounterfeiting technologies and approaches will not be put aside. For example, BIO supports FDA's facilitation of a uniform national electronic pedigree/track-and-trace system. According to the FDA press officer, the agency recognizes that more than one anticounterfeiting measure is needed to combat global counterfeiting and advocates a multilayer approach that involves all parties in the supply chain, from manufacturers to pharmacists. 

Both BIO and PhRMA asserted that details about PCIDs should remain confidential, especially if they are included in new drug or biologic license applications, because large numbers of people see these documents. "Without protection," said PhRMA in its comments, "counterfeiters are more likely to be able to circumvent the anticounterfeiting measure by reverse engineering the product. Hence, disclosure of the PCID (e.g., on the drug product labeling and/or package insert) becomes counterproductive [although we do acknowledge the resulting complexity of not listing an additive that may cause adverse events (e.g., allergic reactions) in a small number of patients]." BIO recommended in its comments that PCID information be included in drug master files as an alternative. 

FDA is working on a final guidance document. In related news, regulatory authorities in Europe are aiming to tighten safety standards for colorants, food additives, and other excipients used in drug products by encouraging the use of more natural-based ingredients. 

's June 2010 Report from Europe will cover the full story.  

Articles

New Draft Guidance for Solid Oral Dosage Forms Focuses on Physical Chemical Identifiers. This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."

FDA Guidance Addresses Anticounterfeiting Measures

Last week, after several years of debate and review, the US Food and Drug Administration called for metered-dose inhalers to be removed from the market. Seven such inhalers, largely used to treat asthma and chronic obstructive pulmonary disease (COPD), use ozone-depleting chlorofluorocarbons (CFCs) to propel the medication into the user’s lungs.

Except for certain uses such as for metered-dose inhalers, the US government eliminated the production of CFCs by early 1996. This measure complies with the international Montreal Protocol, which the US signed in 1987, and the US Clean Air Act of 1990, both of which aim to protect the environment and public health from the potentially negative effects of ozone depletion.

 FDA proposed phasing out the seven inhalers-the only remaining CFC-containing products on the market-in 2007, according to an FDA 

 The agency reached a final decision about the products after reviewing more than 4000 public comments and information submitted as part of a public meeting, according to the release. Alternative drug products that do not contain CFCs will remain on the market.

FDA posted a list on its website of the affected inhalers and the last date that each will be manufactured and distributed throughout the US. The list includes Tilade (nedocromil) and Alupent Inhalation Aerosol (metaproterenol), which will be phased out on June 14, 2010. Azmacort Inhalation Aerosol (triamcinolone) and Intal Inhaler (cromolyn) will not be produced after Dec. 31, 2010. Aerobid Inhaler System (flunisolide) will be phased out June 30, 2011. Finally, Combivent Inhalation Aerosol (albuterol and ipratropium in combination) and Maxair Autohaler (pirbuterol) will not be produced after Dec. 31, 2013.

FDA advises patients using the phased-out products to talk to their doctor about switching to an alternative treatment. “During this transition, FDA wants to ensure that patients have access to safe and effective alternative medications to treat their asthma or COPD,” said Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in FDA’s Center for Drug Evaluation and Research. “We are currently working with professional societies and patient organizations to make sure patients understand which products will no longer be available and have information on which alternative medication might work best for them.”
  

Dry Powder Inhalers: Challenges and Goals for Next Generation Therapies 

After several years of debate and review, the US Food and Drug Administration is calling for the removal of metered-dose inhalers.

FDA Removes Last CFC Inhalers from the Market

Next week, the US Pharmacopeial Convention (USP) will hold its governance meeting-which takes place every five years-in Washington, DC. Convention delegates will meet to set and revise the organization's policy and operational direction for the coming five years. 

One agenda item for the meeting, which will take place April 21–24, is electing new members to the USP Board of Trustees. The Board will guide USP’s work between 2010 and 2015. Among the nominees are Timothy R. Franson and Douglas E. Rollins for president; John E. Courtney and Amy Porter for treasurer; and Duane M. Kirking, John W. Mauger, Mario Rocci, Jr., and Marilyn K. Speedie for trustee representing the pharmaceutical sciences.

The USP Resolutions Committee is expected to present nine resolutions to the delegates for adoption. Resolutions 2 and 3 call for strengthening the organization’s compendial role, including increasing and improving collaboration with the US Food and Drug Administration. “While USP and the agency have worked well together to respond to recent public-health crises, a closer, more forward-looking collaboration with FDA is needed to improve and expand the standards in the 

,” states the proposed resolution. Goals would include closely and jointly scrutinizing 

 monographs with the aim of anticipating and preventing public-health crises. Resolution 3 also suggests the establishment of a pilot program with FDA’s Office of Generic Drugs to focus on reducing abbreviated new drug application backlogs.

Resolution 5 focuses on increasing international harmonization and provides reference to a 2008 

 on the ideal pharmacopeia. The full proposed resolutions are described on the 

Delegates also will discuss proposed changes to the USP bylaws, including structural changes to USP committees and voting membership. One proposal recommends keeping only four of seven convention committees: the Council of the Convention committee, a new Governance committee, a Nominating Committee for Officers and Trustees, and a Nominating Committee for Council of Experts. Another proposal calls for reducing the number of trustees. All of the Constitution and Bylaws committee's proposed changes can be found on the 

The four-day convention and symposium will feature speakers from the US Food and Drug Administration, including Commissioner Margaret Hamburg, the CEOs of the American Medial Association and American Pharmacists Association, and the director of the National Institutes of Health. Distinguished professors presenting at the event will include the University of Maryland’s Rita R. Colwell, the 2010 Stockholm Water Prize winner, and Johns Hopkins University’s Peter C. Agre, a Nobel laureate in chemistry.

 will publish a report about the convention in its May 2010 issue.

The US Pharmacopeial Convention will hold its governance meeting next week in Washington, DC.

USP Convention to Reshape Organizational Structure and Goals

The European Medicines Agency’s Management Board highlighted and praised the European medicines regulatory network's handling of the 2009 H1N1 swine-flu pandemic, according to a Mar. 26, 2010 

. Meeting last month, the board noted that the network allowed the agency, now known as the EMA, to contribute to the European Union response with timely scientific opinions that lead to the approval of three pandemic vaccines and new recommendations for antiviral medicines, says the release.

EMA also noted that it witnessed substantial increases in core areas throughout 2009, including scientific-advice requests (20%), orphan designations (38%), Type II variations (20%), and safety-related activities. The number of applications for marketing authorizations for medicines for human use received was 60% higher than expected. 

Looking ahead, the executive director of the EMA board noted several priority items for 2011. According to the release, these include: efficient management of the core business; monitoring of the safety of medicines and ensuring continuous positive benefit-risk balance; continued involvement of patients and healthcare professionals; responding to globalization of manufacturing and research activities; and responding to public health needs, such as antimicrobial resistance and medicines for the elderly. In addition, EMA intends to further increase transparency of its daily operations by publishing minutes of scientific committee and working-party meetings. 

EMA expects 52 marketing authorization applications for new medicines and 56 applications for generic and hybrid medicines in 2011, as well as 170 applications for orphan designation. The management board’s draft budget for 2011 is € 218.9 million (approximately $294 million), an increase of €20.7 million from 2010. 

The European Medicines Agency's Management Board praised the European medicines regulatory network's handling of the 2009 H1N1 swine-flu pandemic.

EMA Highlights 2009 Accomplishments and Looks Ahead

Seventeen pharmaceutical markets are now ranked as “pharmerging,” according to market-research firm IMS Health. Previously, only seven markets held this title: China, Brazil, Mexico, India, Russia, South Korea and Turkey.

Pharmerging Shake-Up: New Imperatives in a Redefined World

, predicts that 17 countries together will expand by $90 billion between 2009 and 2013, contributing 48% of annual pharmaceutical market growth, up from 37% last year. Behind the change is the global economy and the healthcare environment as well as the growth of the generic-drug market, says the report.  This complex transformation has moved full force since 2006 when IMS first released its seven-country pharmerging market list.

“With a raft of pharmerging countries rapidly gaining market share, we’re seeing a new world order take hold within the pharmaceutical industry,” said Murray Aitken, senior vice-president at IMS’ Healthcare Insight, in an IMS

. The firm has broken down the 17 countries into three tiers. China is the only country in the first tier as it stands “in a league of its own,” according to the report. The country is expected to become the world’s third-largest pharmaceutical developer as soon as next year with $40 billion in growth through 2013.

The second tier includes Brazil, India, and Russia, which are expected to add between $5 billion and $15 billion in annual sales by 2013. The third tier, referred to as “fast followers” by IMS include: Venezuela, Poland, Argentina, Turkey, Mexico, Vietnam, South Africa, Thailand, Indonesia, Romania, Egypt, Pakistan, and the Ukraine. These 13 countries are expected to contribute between $1 billion and $5 billion each in annual sales growth by 2013. (Note: IMS reclassified South Korea as a “developed” market based on its current level of gross domestic product so it is no longer in the pharmerging market list.) Overall, these pharmerging markets are expected to be the biggest contributor to global growth in the next five years.


On the other side of the scale, IMS Health notes that mature pharmaceutical markets such as the US are experiencing lower sales growth based on patent expiration, increased generic-drugs on the market, underfunding of the biotechnology industry, and stricter regulations. Despite the change, IMS predicts that the US and Japan will still hold the first and second spots in its ranking of global pharmaceutical markets in 2013. China, however, will boot out France for the third spot. Germany is expected to hold at the fourth spot.

The dramatic change in the rank of markets should “bring a renewed sense of urgency to the management agenda of an industry already under pressure,” states the report. Manufacturers will need to reassess their geographic portfolios, including not only acknowledging the changing global market but also embracing and adapting to it," says IMS. “With the right fundamental sin place, and the ability to fulfill tactical execution efficiently, they can be positioned to pursue and leverage the pharmerging markets as the major source of growth they represent.”

Seventeen pharmaceutical markets are now ranked as "pharmerging," according to market-research firm IMS Health.

Seventeen, Not Seven, Markets Now Hold "Pharmerging" Title

The US Food and Drug Administration issued a 

Dosage and Administration Section of Labeling for Human Prescription Drug and Biological Products-Content and Format

, to help new drug applicants write the dosage and administration section of their products' label. The guidance provides recommendations about the types of information to include, the format for the section, and when to include information from other labeling sections.

 In addition to basic dosing information such as the recommended starting dose and route of administration, the guidance discusses information that should be included regarding monitoring, safety modifications that need to be made because of drug interactions, and modifications required for certain patient populations such as children. The guidance calls for even more detail regarding dosage compliance. For example, the guidance states, “If it is particularly important that doses be given 8 hours apart…the section should explain the importance of 8-hour spacing of doses.”
  
 Other components of the dosage and administration label should address premedication information and key administration instructions such as whether the drug is light-sensitive or should not be crushed or chewed.

FDA issued a new guidance for industry to help new drug applicants write the dosage and administration section of their products' labels.