The U.S. Food and Drug Administration is announcing the initiation of the Secure Supply Chain Pilot Program to enhance the security of imported drugs. In August 2013, the FDA published a notice in the Federal Register (78 FR 51192) to solicit companies to voluntarily submit applications for participation in this two-year program. Thirteen prequalified companies have now been designated to take part, and will receive expedited entry for the importation of up to five selected drug products into the United States.

The goal of the program is to enable the FDA to evaluate resource savings that will allow the agency to focus imports surveillance resources on preventing the entry of high-risk drugs that are the most likely to compromise the quality and safety of the U.S. drug supply.

"By creating incentives for manufacturers to adopt best practices for supply chain integrity, we can enhance the quality and safety of imported drugs," said Carol Bennett, acting director of the Office of Compliance in the FDA's Center for Drug Evaluation and Research.  "The program also allows the FDA to focus resources on the areas with the greatest potential risk to consumers."

During these next two years, the FDA will evaluate the program's effectiveness at enhancing imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA determines the program to be effective, a more permanent program may be established and possibly extended to additional participating companies.

The following prequalified companies have been accepted into the program and will receive expedited entry:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of the 13 companies met multiple participation conditions, including:

• Committing  to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA);
• Having a validated secure supply chain protocol per the U.S. Customs and Border Protection's Customs-Trade Partnership Against Terrorism (C-TPAT) program;
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products;
• Having effective recall and corrective action plans in place; and,
• Maintaining control over their drugs from the time of manufacture abroad through entry into the United States.

For more information about the program, visit the FDA web site.

The FDA recently published a list of draft guidances that CDER (Center for Drug Evaluation and Research) is planning to publish during 2014. Here is a list of guidances that we think will be particularly interesting.

CATEGORY — Quality: Facility, Production and Process Control

• Contract Manufacturing Arrangements for Drugs: Quality Agreements
• GxP Consideration for Outsourced IT (Cloud Computing) Systems in Medical Product Manufacturing and Clinical Study Environments
• Interim Good Manufacturing Practice for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug and Cosmetic Act
• Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice

The guidance relating to Contract Manufacturing Arrangements for Drugs is eagerly sought after by industry and will arrive approximately one year after the EU’s new cGMP regulations came into effect. It will apply to any organization involved in processing, packing, holding, labelling operations, testing and operations of the Quality Unit when it comes to “active pharmaceutical ingredients (APIs or drug substances, or their intermediaries), finished drug products, combination products and biological drug products”.

It also notes that quality agreements should be in force not only for manufacturing facilities, but also with organizations involved in cGMP activities such as the following:

• Contracted laboratories
• Contracted warehousing & distribution facilities
• IT vendors hosting cGMP related data

We will bring you a more detailed analysis of each guidance upon publication.

An interesting article from FDAzilla alerts non-U.S. pharmaceutical plants to the increase in the number of FDA inspections, and the difference in inspection standards for foreign and U.S. companies.

The FDA is rapidly scaling up the number of inspections it conducts of foreign drug making plants. This year, the agency plans to complete about 2,000 international inspections, and the evidence suggests that this number will continue to grow in FY13.

Avoiding 483s in this environment may be tougher than in American plants, since the agency has more leeway than it does in the U.S. While its authority to inspect U.S. facility comes from Section 704 of the Food, Drug and Cosmetic Act--which requires it to defend its actions pretty thoroughly---its ability to inspect foreign plants comes from Section 801 of that Act. Under Section 801, the agency notes, officials are "not required to provide stringent documentary evidence to establish violations." In other words, the standards for U.S. and foreign inspections differ significantly.

Read the full article

The FDA has published a list of upcoming regulations it plans to issue in the next year. The complete list is available here. Of these regulations, following is a list that will have relevance for the pharmaceutical and medical device industries:

1. Title: Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Food for Animals

Abstract: FDA is proposing regulations for preventive controls for animal food, including ingredients and mixed animal feed. This action is intended to provide greater assurance that food marketed for all animals, including pets, is safe.

2. Title: Amendment to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals--Second Phase

Abstract: FDA will revise regulations for "current good manufacturing practice" for oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products. This revision will update and harmonize requirements and improve detection and response to emerging product safety and quality signals.

3. Title: Amendments to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals--Components

Abstract: FDA will revise regulations for "current good manufacturing practice" with regard to the control over components used in manufacturing finished pharmaceuticals.

4. Title: Proposal to Ban Powdered Natural Rubber Latex and Powdered Synthetic Latex Surgeon's and Patient Examination Gloves

Abstract: FDA has determined that a subset of surgeon and patient exam gloves that are powdered and that represent a modest share of the market present a substantial risk of illness that cannot be corrected by a change in labeling. These gloves are Powdered Natural Rubber Latex Surgeon's Gloves, Powdered Synthetic Latex Surgeon's Gloves, Powdered Natural Rubber Latex Patient Examination Gloves, and Absorbable Powder for Lubricating a Surgeon's Glove. Consequently, FDA is proposing to ban these devices.

5. Title: Postmarket Safety Reporting for Combination Products

Abstract: The rule would describe the postmarket safety reporting requirements for combination products (combinations of a drug, device, and/or biological product). The rule would clarify that a combination product is subject to the reporting requirements associated with the type of marketing application under which the product is approved, licensed, or cleared, and to certain additional, specified reporting requirements depending on the types of constituent parts (drug, device, or biological product) of which it is comprised. The regulation would ensure the consistency and appropriateness of postmarket safety reporting for combination products while minimizing duplicative reporting requirements.

When these regulations are issued, GxP Systems will bring you an in-depth analysis on the impact the revised regulations will have on the pharmaceutical and medical device industries

At long last, the final rule on good manufacturing practice (GMP) requirements for combination products will be published in the January 22, 2013 Federal Register. An advanced display copy of the final rule is available athttp://www.fda.gov/downloads/CombinationProducts/UCM336194.pdf. The rule is effective in 180 days from the publication date, which should be July 21, 2013.

The language of the final regulation is nearly identical to the proposed rule published in 2009, which itself was largely based on a 2004 draft guidance document. The differences between the proposed and final regulations do not impact the actual requirements or framework for how GMPs should be handled (see overview below), but rather are limited to a few areas where wording was clarified or simplified, especially with regard to HCT/Ps (human cellular/tissue products). For example, the final regulation clarifies that an HCT/P that is not solely regulated under section 361 of the Public Health Service Act may be a constituent part of a combination product, but HCT/Ps were removed as a “stand alone” type of constituent part from the definition of “type of constituent part,” which is now limited to drugs, devices or biological products.

The preamble to the final regulation clarifies some issues in response to comments received on the proposed rule. Issues clarified in the preamble include: (1) how demonstration of compliance may be achieved; (2) GMP requirements for investigational combination products; (3) applicability to “legacy” products; (4) applicability to “convenience kits;” (5) applicability to products manufactured at multiple facilities; (6) applicability to drug and device components; (7) clarification of “product specific” vs. “facility specific” GMP requirements; (8) application of design controls; (9) use of an “off the shelf” product as a constituent part of a combination product; (10) clarification of the calculation of yield, reserve sample, batch release, and stability requirements; and (11) Agency expectations regarding communication between manufacturers making different constituent parts of a combination product.

FDA defers to future guidance (not yet released) that will further clarify a number of issues. The timing for release of the guidance document is not stated, but our hunch is that it will be soon, likely to be at least a few months prior to the effective date. Topics FDA notes will be further clarified in the guidance include: (1) how to comply with the rule; (2) distinctions between devices and container/closures; (3) examples to help illustrate the rule; (4) clarifications of sample retention, batch release and stability requirements; (6) coordination among manufacturers with respect to GMP compliance for changes to constituent parts of combination products; and (7) design controls.

Below is an overview of the requirements. Note that these requirements primarily affect single-entity (e.g. drug-coated device) and co-packaged combination products. In contrast, combination products where the constituent parts are separately manufactured and packaged (e.g. cross labeled combination products) each remain subject to their respective GMP requirements and are generally not impacted by this rule.

The final combination product GMP regulation sets forth FDA’s view that drugs, devices and biological products do not lose their individual regulatory identities when they become constituent parts of a combination product. Therefore, the GMP requirements specific to each constituent part of a combination product also apply to the combination product itself.

However, the rule recognizes that 21 CFR 210 and 211 (for drugs and biologics) and 21 CFR 820 (for devices) are similar in most respects. In this context, for single entity and co-packaged combination products, the rule provides a streamlined approach as an alternative to fully implementing and complying with both sets of CGMP requirements. Under this streamlined approach, a manufacturer may choose to operate under and comply with either 21 CFR 210/211 or 21 CFR 820, as an alternative to both, provided that additional specific aspects of the other CGMP framework also are incorporated.

Specifically, a manufacturer choosing to operate under and comply with drug CGMP regulations under 21 CFR 210/211 for its single-entity or co-packaged drug-device combination product also would be considered to have complied with all provisions of the device Quality System Regulation at 21 CFR 820, if it complies with the following specific provisions from 21 CFR 820:

1. 820.20 Management responsibility

2. 820.30 Design controls

3. 820.50 Purchasing controls

4. 820.100 Corrective and preventive action

5. 820.170 Installation

6. 820.200 Servicing

In an analogous manner, a manufacturer choosing to operate under and comply with device CGMP requirements under 21 CFR 820 for its single-entity or co-packaged drug-device combination product, also would be considered to have complied with all provisions of the drug CGMP requirements in 21 CFR 210 and 211, if it complies with the following specific provisions from 21 CFR 210 and 211:

1. 211.84 Testing and approval or rejection of components, drug product containers, and closures

2. 211.103 Calculation of yield

3. 211.132 Tamper-evident packaging for over-the-counter (OTC) human drug products

4. 211.137 Expiration dating

5. 211.165 Testing and release for distribution

6. 211.166 Stability testing

7. 211.167 Special testing requirements

8. 211.170 Reserve samples

 

2. 211.103 Calculation of yield

3. 211.132 Tamper-evident packaging for over-the-counter (OTC) human drug products

4. 211.137 Expiration dating

5. 211.165 Testing and release for distribution

6. 211.166 Stability testing

7. 211.167 Special testing requirements

8. 211.170 Reserve samples

Combination products that include a biological product or human cellular or tissue (HCT/P) constituent part would need to incorporate relevant biological product requirements under 21 CFR 600-680 or 21 CFR 1271, respectively.

Finally, for combination products where the constituent parts are separately manufactured and packaged (21 CFR 3.2(e)(3) and (e)(4)), under the proposed rule, each constituent part would remain separate for purposes of applying the CGMP regulations. For example, for a combination product comprised of a drug and a cross-labeled but separately packaged delivery device, the drug constituent part would be subject to 21 CFR 210 and 211, while the delivery device would be subject to 21 CFR 820.

Finally, for combination products where the constituent parts are separately manufactured and packaged (21 CFR 3.2(e)(3) and (e)(4)), under the proposed rule, each constituent part would remain separate for purposes of applying the CGMP regulations. For example, for a combination product comprised of a drug and a cross-labeled but separately packaged delivery device, the drug constituent part would be subject to 21 CFR 210 and 211, while the delivery device would be subject to 21 CFR 820.

The Cork Chamber of Commerce held its Annual Conference this week at the scenic Fota Island Resort. The theme for this years’ conference was “Winning in the UK & Beyond”. I attended along with GxP Systems Business Development Manager, Denise Manton.

The event was chaired by well-known Irish broadcaster Anton Savage, who introduced our first speaker, President of the Cork Chamber of Commerce Gillian Keating. Gillian offered a wise thought when introducing proceedings: “Never mind the recession, there are opportunities in the UK”. I found this great motivation and relevant for any company who have a product or service for export, like my own.

Steve Aiken, CEO of British Irish Chamber of Commerce, spoke next. Steve told how businesses in London, Manchester and Birmingham, all locations with a fast growing manufacturing industry, want to do business with Irish companies. Indeed, the UK is home to over 40,000 Irish people who themselves are leaders in business. This offers a significant opportunity to Irish companies wishing to access the UK market.

Hugo MacNeill, MD Goldman Sachs Ireland, was our third speaker. When asked to highlight the differences between the UK and Ireland, he said that there are none really. He asked everyone attending “Are you maximising your potential in the UK? If not, then you can”.

He spoke of the importance of events like this conference 

hat highlight challenges companies face when entering new markets and bring groups together to provide insights in how specific challenges can be overcome. As well as being able to “talk the talk”, it’s vital in the UK that you “walk the walk” – certainly, delivery on customer expectations is what GxP Systems is all about.

Sharon Buckley, Group Commercial Director, Musgrave Group followed. Founded in Cork in 1876, The group now has an annual turnover of €4.9bn. Sharon spoke on how the Musgrave Group played to local community strengths when entering the UK market; because the UK and Ireland are so similar, most of the solutions to overcoming challenges are common to both. They initially adopted a partnership approach, which allowed them to gain an Insight into how the UK market functioned. After discovering that there was no real difference between Ireland and UK, they grew through a combined approach of organic growth and acquisition.

Our next speaker, Finbarr Whyte, VP & Site Director of GlaxoSmithKline Cork, provided insight as to what multi-nationals look at when investing in Cork. GSK have invested €670m in Cork since 1974 so his thoughts were always going to be relevant and insightful. He spoke on what is important to GSK as a corporate entity:

• Security of supply
• Compliance
• Sustainability & corporate social responsibility
• Fiscal efficiency
• Competitive cost base
• Flexible skilled workforce

Cork provides all of these factors, and it is important to continue to do so in order to keep attracting large scale investment.

Some of the challenges faced by GSK Cork are:

• Developed markets are not growing while emerging markets are increasing
• UK patent ban: 10% tax rate relating to profits from sales of innovative products (very relevant to any pharma/med device manufacturers who currently pay a higher rate of tax)
• Reduced take-up of science in Irish 2nd & 3rd level educational institutions
• Increasing cost of doing business here

Finbarr also noted GSK Cork successes:

• Winning contract to produce Gantrez (an ingredient in Colgate toothpaste)
• Winning contract to produce other third party products
• Receiving planning permission to build a wind turbine at Cork facility allowing them to become self sustainable
• Receiving approval to begin production of their own range of opiates

Julie Lynes, founder of EZ City, followed Finbarr Whyte. Julies’ advice, herself having recently entered the UK market, was most practical:

• Test the market
• Have a structured plan
• Have defined goals
• Research your market

Above all, “You need belief on your product and service” advised Julie.

An interesting panel discussion followed, hosted by Anton Savage, where audience members were permitted to ask questions of the panel of speakers. Questions ranged from “Who are the people to contact to begin my market research?” (British Irish Chamber of Commerce) to “What was the first step you took when you decided to trade in the UK” (buy a UK mobile phone). Each speaker was highly motivational and gave great food for thought.

The morning was capped off by a presentation from Denis Kennelly, VP Security Systems Development IBM. Denis spoke of how IBM have altered their business plan and sold the PC manufacturing side of their business to focus on IT solutions and services. When entering new markets, he said it is important to consider the following:

• What makes my product unique?
• How does my price compare to competitors?

Most companies, when entering a new market, assume that their success in their current market will automatically carry over to a new market with little or no adjustment. It’s important to treat your entry in a new market as if you were setting up the business from scratch.

The final speaker was H.E. Dominic Chilcott, British Ambassador to Ireland. Ambassador Chilcott spoke of the close ties between UK and Ireland and stated that the relationship between both countries has never been better. Ireland is a more important market to UK than China, Brazil, or India because of greater exports. UK companies like doing business with Ireland because of the excellent products and services offered here.

The event certainly showed the benefits of entering the UK market and particularly how important it is to do so. GxP Systems are looking forward to expanding operations in UK over the coming months and are well equipped to face all the challenges associated with this.

By Damien Hanley
Marketing Specialist, GxP Systems