Rx-360 Issued: May 10, 2013

The United Nations Office on Drugs and Crime published a report in April 2013 titled Transnational Organized Crime in East Asia and the Pacific.  This report addresses the flow of twelve types of illegal movement of materials that are part of organized crime activities in East Asia and the Pacific region.  The report does not, in general, address materials moved from East Asia to the US and Europe.  

These twelve can be grouped into four larger areas of “contraband flows” that includes:

• Smuggling of people for labor, sexual exploitation and migration.
  
  
• Movement of drugs including opiates (Myanmar and Afghanistan) and methamphetamines.
  
  
• Environmental items including illegal trade in wildlife, electrical and computer waste, and ozone depleting substances.
  
  
• Movement of counterfeit consumer goods from East Asia to the US and Europe and movement of fraudulent medicines from East Asia to Africa and Southeast Asia.

The report recognizes that a successful resolution to the problems will require a global approach because much of the activity, including movement of money,  crosses multiple country borders.

To view or download the UN Report, click here

To view or download the Rx-360 Summary of the
UN Report, click here

Rx-360 Issued: May 10, 2013

FreightWatch 2013 Global Cargo Theft Threat Assessment provides a 70 page risk assessment of global cargo theft.  The report addresses the diverse scope of cargo types including but not limited to alcohol, auto parts, clothing, electronics, jewelry, pharmaceuticals and metals.  The report includes regional data for North America, Central and South America, Europe, Africa and Asia.  Within each region, countries are addressed individually.  

The report includes excellent graphics of theft identified by product type, high risk highways/regions/cities, and trends and techniques for how theft is executed within specific areas.  Some interesting statistics include:

• Theft of pharmaceuticals constitutes 3% of the thefts in the US, 30 overall in 2012.  Texas was the site of 7 (23%) of the events. 
  
  
• In Europe, the highest number of cargo thefts occurred in Germany, with 31% of those thefts focused on the building/industrial sector.  In Italy, pharmaceuticals accounted for 37% of cargo thefts, with clothes and shoes in second place at 17%.
  
  
• Cargo thefts in Brazil continue to be violent with shootouts not uncommon.  Mexico is increasingly becoming more violent, but remains less violent than cargo thefts in Brazil.
  
  

To view or download the FreightWatch Report, click here

To  view or download the Rx-360 Summary of the
FreightWatch Report, click here

Rx-360 Issued: May 1, 2013.

This chart has been prepared by Rx-360 to include updates on the actions of regulatory authorities with regards to implementation of the Falsified Medicines Directive Written Certification Requirement. 

Rx-360 makes every effort to ensure that this information in this chart is accurate as at the date of issue. Changes in law or circumstances may occur after the issue date which may make the information no longer accurate. Rx-360 will periodically update the information, reflecting the new date of issue. Please email megan.cahill@dbr.com with new information that could be included in this chart. 

Rx-360 Issued: April 29, 2013

On April 25, 2013 the Energy and Commerce Committee of the US House of Representatives conducted a hearing entitled Securing Our Nation’s Prescription Drug Supply Chain.

 

Several hearings on this topic have been held in the past few years.  The FDASIA bill passed last summer institutes some additional requirements for control of the pharmaceutical supply chain, but serialization and track/trace aspects were notably absent.  

Both the House and Senate have put forth draft discussion versions of bills addressing this topic, and have very tight turnaround time for securing input from stakeholders.  Included here are links to a background memo, discussion draft of the legislation and testimony presented at the hearing including that by Janet Woodcock, the Director of the Center for Drug Evaluation and Research at FDA.  Those who have been following this legislation and earlier hearings will recognize some of the participants including Allan Coukell from the Pew Health Group and Christine Simmon from the Generic Pharmaceutical Association.

 

To watch a video of the entire proceedings, click here

 

Information presented and can be viewed or downloaded using the following links:

• Background Memo
  
  
• House of Representatives Discussion Version of a proposed bill addressing supply chain security
  
  
• Janet Woodcock, Director of the Center for Drug Evaluation and Research, FDA, testimony
  
  
• Elizabeth Gallenagh, VP of Government Affairs and General Counsel Healthcare Distribution Management Association, testimony
  
  
• Elizabeth Gallenagh Testimony's Supporting Documentation
  
  
• Christine Simmon, Senior Vice President, Policy and Strategic Alliances, Generic Pharmaceutical Association, testimony
  
  
• Michael Rose, Vice President Supply Chain Visibility Johnson and Johnson Health Care Systems, Inc, testimony
  
  
• Tim Davis, on behalf of National Community Pharmacists Association, testimony
  
  
• Allan Coukell, Director Medical Programs, Pew Charitable Trusts, testimony
  
  
• Carmen Catizone, Executive Director and Secretary National Association of Boards of Pharmacy, testimony
  
  
• Walter Berghahn, Executive Director, Healthcare Compliance Packaging Council, testimony

Rx-360 Issues: April 27, 2013

The EMA Released Guideline on the use of porcine trypsin used in the manufacture of human biological medicinal products

for consultation on 1 March 2013.  Comments are due to EMA by August 31, 2013.  Trypsin is frequently used in the manufacture of biological medicinal products, primarily to aid the removal of cultured mammalian cells from culture vessels during the expansion of cultures from the cell bank stage.

Guidance has been provided for the use of bovine sera in mammalian cell culture, but no guidance has been issued with regard to the use of products isolated from porcine sources.  This guidance was prompted by a 2010 publication that demonstrated the identification of DNA sequences from porcine circovirus in a human rotavirus vaccine, and identified porcine trypsin as the likely source of the contamination.  The guideline addresses appropriate selection of porcine starting materials for isolation of trypsin, testing for adventitious agents at the appropriate stage(s) of the production of trypsin, incorporation of virus reducing steps during the manufacture of trypsin and validation of virus reduction within the manufacture of the human medicinal product.  The enzymatic nature of trypsin introduces a number of complications into all of these considerations.  Manufacturers are encouraged to use alternative enzymes in place of trypsin where possible.  Finally, the Marketing Authorization Holder / Applicant should provide information demonstrating appropriate levels of control over the trypsin used in manufacture of human medicinal products.   The guideline, when finalized, will not apply to products already on the market, but those MA holders are encouraged to assess the viral safety of their products with consideration to guidance provided here.

To view or download the EMA Guidance, click here.

Rx-360 Issued: April 22, 2013

Importation of Active Substances For Medicinal Products for Human Use, Questions and Answers, Version 4.1 was published by the European Commission on April 17, 2013.  This supersedes version 4.0 published earlier this month.  The only change made to this version was the elimination of the response to question 11b regarding the status of “atypical” active substances.  It was determined that additional consultation was needed with Member States prior to finalizing a response regarding the handling of atypical actives.

The document presented here is the fourth in recent months to address the issue of transportation and distribution of medicinal products: the EMA, Central Drugs Standard Control Organization of India (CDSCO), the China FDA (CFDFA) and now the Saudi FDA (SFDA).  We do not present an analysis of the similarities and differences among the four, but they do serve to stress the important that regulatory authorities place on controlling the distribution of medicinal products.  Appropriate transportation and storage is important both in maintaining the quality of the drugs and ensuring that only authentic products reach patients. 

The Saudi Food and Drug Authority issued a 46-page Guidance for Storage and Transport of Time and Temperature Sensitive Pharmaceutical Products on December 15, 2012.  The guidance was implemented on February 16, 2013. Both EMA and the China State Food and Drug Administration (SFDA) have recently issued updated guidance on similar topics.  The document is divided into chapters covering: 

• Import
• Storage Buildings
• Temperature Controlled Storage
• Materials Handling
• Transport and Delivery
• Labeling
• Stock Management
• General Protocols and Record Keeping

An English translation of the Notification is provided by courtesy of Thomson Reuters Cortellis™ for Regulatory Intelligence.  

To View or Download the Saudi FDA Guidance, click here

To View or Download the Rx-360 SUmmary of the Saudi FDA Guidance, click here

Rx-360 Issued: April 9, 2013

The Food and Drug Administration (FDA) is announcing the establishment of a public docket for comments pertaining to the implementation of its administrative detention authority with respect to drugs under the Food and Drug Administration Safety and Innovation Act (FDASIA). This document is intended to solicit input from all relevant stakeholders before FDA issues regulations to implement its administrative detention authority with respect to drugs and to announce that such information submitted to FDA is available to all interested persons in a timely fashion.

On April 3, 2013 FDA published a Draft Guidance for Industry “Glass Syringes for Delivering Drug and Biological Products:  Technical Information to Supplement International Organization for Standardization (ISO) Standard 11040-4”.  

Rx-360 Issued: April 5, 2013

Comments are due to the Agency by July 2, 2013.  This guidance applies to both syringe manufacturers and manufacturers of combination products using these syringes.  Briefly, FDA has identified quality issues and adverse events associated with some glass syringes used with “connecting devices” that can result in delay of medication delivery to patients in emergency situations.

They have now determined that compliance with this standard is not sufficient to ensure a proper connection. FDA recommends that sponsors submit additional data in their filings that goes beyond the requirements of ISO-11040-4.  Pages 6-11 identify the FDA recommendations regarding design or redesign of the syringe itself and information to be provided on the combination product where the syringe is filled with a drug or biologic.  Information should be submitted to the relevant IDE, 510(k) or PMA or to the IND/NDA/BLA/ANDA for combination products.

To view or download the draft guidance, click here

China SFDA Published a Good Supply Practice Guidance

Rx-360 Issued: March 29, 2013

On January 22, 2013 the China SFDA published a Good Supply Practice guidance that will be implemented on June 1, 2013. Businesses will have a 3 year period to phase in the requirements and if this has not been accomplished by the deadline in 2016 they will be required to cease their activities. This is another demonstration that China is working diligently to upgrade the quality of their pharmaceutical manufacture and distribution networks.  

The guidance significantly increases the requirements for Quality Management.  The relevant chapters include: General Provisions, Drug Wholesale Quality Management, Drug Retail Quality Management, and Supplementary provisions.  Significant emphasis is placed on the standards to be implemented for computerized hardware and software systems.  The use of controlled computerized systems is intended to both be an aid in protection of drug quality but will also serve as a barrier to entry into this part of the pharmaceutical business.

To view or download the
SFDA Good Supply Practice Decree, click here

To view or download the
SFDA Good Supply Practice guidance, click here

To view or download the Rx-360 Summary
of the SFDA Good Supply Practice guidance, click here

The EMA has released the draft revisions to four GMP Guideline Chapters for consultation (Chapters 3, 5, 6 and 8).  Comments are due to EMA on 18 July 2013.  The proposed changes to each chapter are briefly summarized below based upon information from the EMA web page.

Chapter 3, Premises and Equipment has a revised Section 6 that addresses the prevention of cross contamination.  This topic is also addressed in Chapter 5. Reference is made to the recently released guidance on toxicological assessments relative to setting carryover limits in shared facilities and equipment that should be considered for both Chapters.

Chapter 5, Production has revisions to the following sections:

• Sections 17-20 address cross contamination and toxicological assessment guidance referenced above.
• Sections 26-28 address the legal obligation of the Manufacturing Authorization Holder to ensure that active ingredients are manufactured in accordance with GMP and assurance of supply chain traceability.  These requirements come from the 2011 Falsified Medicines Directive requirements.
  
• Section 33 clarifies what is expected relative to testing of starting materials.
  
• Section 68 addresses notification of regulatory authorities of potential drug shortages.
  

Chapter 6, Quality Control Sections 37 thru 41 address expectations regarding technology transfer of analytical methods.

Chapter 8, Complaints, Quality Defects and Product Recalls, has been revised to reflect:

• Incorporation of Quality Risk Management principles when investigating defects and complaints and making decisions on recalls or mitigation actions.
• Investigations should be conducted to identify the cause of the defect and actions should be put in place to prevent or minimize its recurrence.
  
• Clarification regarding the reporting of Quality defects to the proper authority.

To view or download Chapter 3, click here

To view or download Chapter 5, click here

To view or download Chapter 6, click here

To view or download Chapter 8, click here

Rx-360 Summary of the New EC GDPs

Rx-360 Issued: 20-March-2013

The EC published their revised Guideline on Good Distribution Practice on March 7, 2013.  The effective date for its implementation is six months post publication.  This guideline revises one that has been in place for nineteen (19) years.  Some, but not all, of the new areas covered in this guideline are as follows:

• Chapter 1, Quality Management addresses change control, CAPA and Quality Risk Management for Wholesale distributors.
  
  
• Chapter 2, Personnel addresses the duties of the Responsible Person, training requirements for staff, and consideration of a hygiene requirement.
  
  
• Chapter 3, Premises and Equipment specifies qualification requirements for key equipment, record retention for key equipment, and specific requirements associated with computer system validation.

•  Chapter 4, Version control is required to ensure that procedures are up to date, and documents should be written in a language readily understood by personnel.

• Chapter 5, Operations expands on requirements to verify “bona fides” of suppliers and customers and now covers export.  This section has been expanded significantly from the previous version.
  
  
• Chapter 6, Covers complaints, returns, suspected falsified medicinal products and medicinal product recalls.
  
  
• Chapter 7, Describes controls that should be in place when outsourcing of GDP activities.
  
  
• Chapter 8, Self-Inspections now allows that these may be conducted by independent auditors, other than the Responsible Person and suggests incorporation of CAPA principles in the audit remediation.
  
  
• Chapter 9, Transportation also was significantly expanded to include the requirement for shipment at label conditions, contract with transport carriers, a preference for dedicated transport vehicles, and risk assessment of transport routes.
  
  
• Chapter 10, Specific Provisions for Brokers provides requirements for brokers, something that was not covered in the previous version of the guideline.
   

To view or download the EC GDP guidance document, click here

To view or download the Rx-360 Summary, click here

Summary of the SFDA Notification on Matters Related to the Implementation of Electronic Monitoring of Imported Drugs

Rx-360 Issued: 12-March-2013

The State Food and Drug Administration (SFDA) of China published a Notification on Matters Related to the Implementation of Electronic Monitoring of Imported Drugs on January 29, 2013. This document is intended to assist in implementation of the SFDA Electronic Monitoring efforts.  

Companies that import drugs into China are to identify an agent in China to act as their representative with regard to electronic monitoring requirements and this agent shall function as the contact with China’s drug administration departments regarding electronic monitoring, data, and recalls.  Barcodes for electronic monitoring are to be in use by January 1, 2014; however it appears there may be some flexibility for import of product that is not barcoded until April 4, 2014.  The Notification summarized in the slide deck includes two appendices, one that must be completed to identify the electronic monitoring Agent and another form that is to be completed when a change in such agent is made.  An English translation of the Notification is provided by courtesy of Thomson Reuters Cortellis™ for Regulatory Intelligence.  

To view or download the Guidance document, click here

To view or download the Rx-360 Summary, click here

Rx-360 Summary of IOM Report: Countering the Problem of Falsified and Substandard Drugs

Rx-360 Issued: February 26, 2013

In 2011, the FDA requested that a committee at the Institute of Medicine (IOM) evaluate how fake medicines and medicines of poor quality impact the public health.  The committee was instructed to evaluate this issue from a global perspective, and not just limit the assessment to the impact on the United States.  

The IOM recently published their report (Countering The Problem of Falsified and Substandard Drugs) and agreed with FDA’s initial finding that this is a global problem and any resolution will require cooperation among global authorities and countries.  

The report’s findings include:

• Failure to comply with GMPs are often the root cause of poor quality drugs;
• Poor quality or fake medicines often fail to help patients and can frequently cause harm;
• Crime drives the business of falsified medicines and this is more common in undeveloped countries that do not have a robust regulatory authority or legal system to enforce requirements ensuring the quality of drugs;
• Complicated supply chains contribute to the problem and must be addressed in any proposed solution;

FDA is encouraged to work with international partners in seeking a resolution.  The IOM report further urged Congress to pass track and trace legislation to monitor drugs throughout the supply chain.

Read FDA Commissioner, Dr. Hamburg's and
US Senators Bennet's and Burr's comments, click here

To read or download the IOM report, click here

To view or download Rx-360 Summary

of the IOM Report, click here

EC Releases Three Guidance Documents for Public Consultation

Rx-360 Issued: 20-February-2013

On February 5, 2012 the European Commission published three documents for consultation.  The first two draft guidelines directly support implementation of the Falsified Medicines Directive (FMD); the third document addresses QP certifications of investigational medicines.  A slide deck has been prepared for each.  The documents include:

To view or download the EC GDP Document, click here
To view or download the Rx-Summary of the EC GDP Document, click here

Guidelines on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use. This guideline supports implementation of a requirement in the FMD that excipients be manufactured under appropriate GMP.   It requires a formal risk assessment and specifies the criteria and attributes that should be considered and documented.   

To view or download the EC Formalized Risk Assessment Document, click here
To view or download the Rx-Summary of the EC Formalized Risk Assessment Document, click here

Template for the Qualified Person’s Declaration Concerning GMP Compliance of Investigational Medicinal Products Manufactured in Non-EU Countries.  Investigational products are out of scope of the FMD.  A footnote in this publication indicates the template is developed to provide consistency and to support requests for clinical trial authorization.   

To view or download the EC QP Declaration Document, click here
To view or download the Rx-Summary of the EC QP Declaration Document, click here

Summary of Food and Drug Administration Drug Shortages Task Force and Strategic Plan – Federal Register Notice

Rx-360 Issued: 11-February-2103

Summary - To assist the Food and Drug Administration in drafting a strategic plan on drug shortages as required by the Food and Drug Administration Safety and Innovation Act, the Agency is seeking public comment from interested persons on certain questions related to drug and biological product shortages. Comments are due by March 14, 2013.

Background – The Food and Drug Safety and Innovation Act requires the formation of a task force to develop and implement a strategic plan for enhancing FDA’s response to preventing and mitigating drug shortages. The plan must include:

• Plans for interagency cooperation
• Plans for ensuring that drug shortages are considered when a regulatory action is initiated that could precipitate or exacerbate a drug shortage
• Plans for effective communication with outside stakeholders
• Plans for considering the impact of shortages on research and clinical trials
• An examination of whether to establish a “qualified manufacturing partner program” as described in the FD&C Act.

Scope of Input Requested – The task forces is seeking comments from the public on the development of this strategic plan, including prevention and mitigation of both drug and biological shortages. The questions are:

• Ideas to encourage high-quality manufacturing and to facilitate expansion of manufacturing capacity
• Since FDA routinely engages with other US government agencies to prevent shortages, are there other incentives that those agencies can provide to prevent shortages?
• Any changes to existing tools that FDA uses to manage shortages? Any other actions FDA can take to improve their utility in managing shortages?
• Any changes or enhancements to tools that FDA uses to communicate shortages?
• What impact do drug and biological shortages have on research and clinical trials?
• Any other actions or activities that FDA should consider including in the strategic plan to help prevent or mitigate shortages?

To view or download the Federal Register Notice, click here

India published a draft Guidelines on Good Distribution Practices for Pharmaceutical Products

Rx-360 Issued: 04-February-2013

The Central Drugs Standard Control Organization (CDSCO) of India published a draft Guidelines on Good Distribution Practices for Pharmaceutical Products for consultation on January 10, 2013.  Comments are due to the agency before January 31, 2013, please see the cover page of the Guideline for the address to which comments should be sent.  

To view or download the Indian GDP Guidance, click here

To view or download the Rx-360 Summary of the Indian GDP Guidance, click here

Rx-360 Issued: January 31, 2013

New Question and Answer documents have been published by the EMA and the MHRA with regard to the GMP confirmation for APIs imported into the EU.  The EMA document is version 3 and reflects updates in interpretation and clarification of details.  The MHRA document addresses the same topic with respect to import of API into the UK. 

On January 28, 2013 the EMA published Version 3 of the Q&A with regard to implementation of the requirement for import of APIs into the European Union as governed under the Falsified Medicines Directive requirements to be effective July 2, 2013. This replaces Version 2 published in October 2012. Changes in the document are:

• The amended response to question 18A clarifies that where a non-EU country issues a confirmation statement based relative to “equivalent GMP standards” on an inspection by another regulatory authority, that inspecting authority should be identified.   
• Two new questions and answers are included, 11A and 19A.  The response to question 11A addresses the situation where API is imported into the EU and the dosage form is for export only.  In this case, written confirmation for the API is required upon import into the EU. The response to 19A clarifies that unannounced inspections by the regulatory authority are not a requirement but should be an option available to the regulatory authority that would be consistent with requirements in the EU.

The MHRA Q&A document was presented at an industry meeting held on November 15, 2012.  It addresses 17 questions including administrative issues specific to the UK, including Customs and Excise processes.  It includes several questions with regard to the need for manufacturers, importers and distributors to register along with information regarding forms required and the length of time it takes to complete registration.  The Q&A clarifies that veterinary products are out of scope.

Additional revision to both documents may be published as interpretations are refined and additional detail on the implementation requirements are finalized.  We will continue to monitor for publication of these documents and will provide updates as available.

To view or download the MHRA Q&A, click here

To view or download the EMEA Q&A, click here