Thursday, October 27, 2016
2011 Index Minimize





Rx-360 Summary of EC Detailed Rules for a Unique Identifier for Medicinal Products for Human use
Guidance 04-Dec-11
Rx-360 Summary of IMB Wholesaler Guidance
Guidance 02-Dec-11
Rx-360 Summary of the FDA's Approaches to Medical Product Shortages
Guidance 29-Nov-11
Rx-360 Summary of Proposed US HR 3026, Safeguarding American’s Pharmaceuticals Act of 2011
Legislation 21-Nov-11
Rx-360 Applauds US Policymakers for Introducing Counterfeit Drug Penalty Enhancement Act
Legislation 18-Nov-11
Rx-360 summary of FDA's final guidance on anticounterfeiting excipients
Guidance 26-Oct-11
Rx-360 Summary of IMB Guide To Storage And Transportation Temperature Conditions For Medicinal Products And Active Substances

Guidance 20-Oct-11
FDA releases final guidance on anticounterfeiting excipients
Guidance 12-Oct-11
IMB Guide To Storage And Transportation Temperature Conditions For Medicinal Products And Active Substances
Guidance 10-Oct-11
Rx-360 Summary of Proposed US Senate Legislation S-1584 Drug Safety and Accountability Act 2011

Legislation 07-Oct-11
Multi-Agency participation in global efforts to protect consumers and patients from unsafe drugs on the internet

Enforcement 30-sep-11
New US Draft Pharmaceutical Supply Chain Leglislation Published 

Legislation 29-sep-11
Rx-360 Summary of FDA Diversion and Counterfeit Criminal Case Information
Benchmarking 28-Sep-11
Rx-360 Summary of WHO Annex 9: Guidance for the storage & transport of time & temp-sensitive products
Guidance 11-Sep-11
Rx-360 Summary of FDA Bar Code Requirements
Guidance 11-Sep-11
Rx-360 Summary of USP  Good Storage and Distribution Practices for Drug Products
Guidance 30-Aug-11
Rx-360's Operating Philosophy Agrees with the PIC/S Q&A on API Distribution Activities
Guidance 04-Aug-11
Rx-360 is Encouraged by the Progress Regulators Have Made Sharing Inspection Findings
Investigations 03-Aug-11
Rx-360 Summary of EU Draft Good Distribution
Guidance 28-July-11
Rx-360 Summary of FDA's Modification of Pedigree Requirements 

Legislation 25-July-11


Rx-360 Summary of New Saudi Arabian GMPs

Regulation 20-July-11
Rx-360 Summary of New EU Batch Certification Requirements
Regulation 15-July-11
Rx-360 Summary of Finalized EU Falsified Medicines Act

Legislation 05-July-11
Rx-360 Summary of US FDA's Pathway to Global Product Safety and Quality

Govt Report 05-July-11
Rx-360 Summary of Turkish GMPs/GDPs and Audit Checklist
Regulation 29-June-11
Rx-360 Summary of US Proposed Leglisation Drug Safety Enhancement Act of 2011
Legislation 28-Apr-11
Rx-360 Summary of Counterfeit Pharmaceutical Inter-Agency Working Group Report to the Vice President of the United States and to Congress
Govt Report 04-Apr-11
Rx-360 Summary of FDA's Final Guidance for Industry, Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products
Regulation 04-Apr-11
Rx-360 Summary of Guidance for Industry, Non-Penicillin Beta-Lactam Risk Assessment

Regulation 24-Mar-11
Rx-360 Summary of European Parliament adopted the amendments on Counterfeit Medicines
Legislation 15-Mar-11
Rx-360 Summary of EMA's draft Qualified Person's (QP) Template and associated Q&A
Regulation 23-Feb-11
Rx-360 Summary of the EMA Road Map 2015
Regulation 10-Feb-11
Rx-360 Summary of Revisions to Annex 11, Compuerized Systems 

Regulation 30-Jan-11
Rx-360 Summary EU Chapter 5 Revisions 
Regulation 07-Jan-11



Delegated Act on the Detailed Rules for a Unique Identifier for Medicinal Products for Human use, and its Verification (18 November 2011) Minimize

Rx-360 Issued: 04-December-2011

The European Commission published an 18-page concept paper on November 18, 2011 titled “Delegated Act on the Detailed Rules for a Unique Identifier for Medicinal Products for Human Use, and its Verification”.  This is a follow up action required by the recently finalized Falsified Medicines Directive which introduces the requirement for safety features, including unique identifiers and their verification.  In this concept paper the EC states “This concept paper is being rolled out for public consultation with a view to preparing both the impact assessment and the delegated act.”  The adoption of the resulting delegated act is scheduled for 2014.  The concept paper poses 5 “consultation items” and asks specific feedback on each of these.  Comments are due by April 27, 2012.

To view or download the EC Concept Paper, click here

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


Guide to Wholesaling of Medicinal Products for Human Use in Ireland (28 September 2011). Minimize

Rx-360 Issued: 02-Dec-2011

The Irish Medicines Board (IMB) recently published a final guidance document entitled “Guide to Wholesaling of Medicinal Products for Human Use in Ireland." This document focuses only on human medical products, and does not include those for veterinary use.  The document includes sections that cover:

  • Applicable legislation.
  • Summary of the EU Guideline on GDP (note that a proposed revision of the EU GDP Guidelines was recently published for consultation and is not yet finalized though the text in this document may lead the reader to conclude otherwise).
  • IMB requirements and policy for wholesale distribution of these products. 

To view or download the IMB Guidance, click here

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


A Review of FDA’s Approach to Medical Product Shortages (October 31, 2011) Minimize

FDA published a report dated October 31, 2011 entitled “A Review of FDA’s Approach to Medical Product Shortages” and are soliciting industry comments.  In the report, the FDA provides facts about the existing situation with drug shortages, actions they are taking both to prevent and respond to drug shortages, and unique features about the shortage of sterile injectable products, generally generic drugs.   The review provides a detailed and highly footnoted review of the situation with graphical representation of product types associated with shortages,  route of administration, reason for the shortages and actions taken by FDA to mitigate shortages.  In addition, FDA describes how each of the relevant centers has addressed shortages in their specific area. 


To view or download the FDA Report, click here

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


US HR3026, Safeguarding American’s Pharmaceuticals Act of 2011 Minimize

Representatives Matheson and Bilbray introduced HR3026, “Safeguarding American’s Pharmaceuticals Act of 2011” on September 22, 2011. This proposed legislation addresses some of the recent requests from the FDA regarding additional authority they would like particularly the ability to destroy counterfeit/adulterated/misbranded drugs at the border and authority for a standard tracking mechanism for prescription drugs.  Some features of the bill include (see details in summary slide set):

  • Authority to destroy counterfeit, adulterated or misbranded drug when it arrives at the border. 
  • Interim provisions to assure safety of the drugs while in the wholesale distribution chain.
  • FDA shall develop Standard Numerical Identifiers with a phased implementation that would include 50% of drugs by January 1, 2015 and all drugs by January 1, 2016.
  • FDA shall develop regulations to establish drug identification and tracking systems that would apply to drug manufacturers, re-packagers, wholesale distributors, and dispensers allowing members of this distribution chain to authenticate the wholesale distribution history of any prescription drug that requires a standard numerical identifier. 
  • The standards relative to documenting identification and tracking shall be federal and not established on a state by state basis.
  • Regulation would be developed to require license of wholesale distributors of prescription drugs.    

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

To view or download the Proposed Leglislation,
click here



Counterfeit Drug Penalty Enhancement Act Minimize

United States policy makers introduced legislation which significantly increase the penalties for the sale, manufacture and trafficking of counterfeit medicines.

Sponsoring the Counterfeit Drug Penalty Enhancement Act are U.S. Senators Patrick Leahy of Vermont, Chuck Grassley of Iowa, Michael Bennet of Colorado, Richard Blumenthal of Connecticut, as well as U.S. Representatives Patrick Meehan of Pennsylvania and Linda Sanchez of California.

The goal of the act is to increase penalties for the trafficking of counterfeit drugs to serve as a deterrent and preventing patient harm.  The proposed legislation would increase the maximum prison sentence for counterfeiting medicines to 20 years for individual first-time offenders, and increase the maximum fine that can be imposed on them to $4m. Repeat offenders would be liable for fines up to $8m, while institutions found guilty of trafficking could be fined $10m for a first offense and $20m for repeat offences.

The legislation responds to recommendations made by the U.S. Intellectual Property Enforcement Coordinator and the administration’s Counterfeit Pharmaceutical Inter-agency Working Group. 

"While it is currently illegal to introduce counterfeit drugs into interstate commerce, the penalties are no different than those for the trafficking of other products, such as electronics or clothing," said Sen. Leahy, who chairs the Senate Judiciary Committee, in a statement.  In addition, Rx-360 has written about and presented on the necessity for stricter criminal penalties, see editorial published in Rx-360 Newsletter in November 2010 entitled “Stricter Criminal Penalties Are Required” by
clicking here.

Several organizations have already praised the draft legislation.  To read the statements praising the draft legislation from the Pharmaceutical Research and Manufacturers of America’s (PhRMA’s),
click here and from Pfizer, click here

In addition, to the praise from PhRMA and Pfizer, Rx-360 would also like to applaud U.S. Senators Pat Leahy, Charles Grassley, Michael Bennet, Richard Blumenthal as well as U.S. Representatives Patrick Meehan and Linda Sanchez for introducing the “Counterfeit Drug Penalty Enhancement Act of 2011.  Rx-360 believes that tough criminal penalties are a necessary deterrent in the prevention of medicinal counterfeiting.


FDA releases final guidance on anticounterfeiting excipients Minimize

FDA published a draft guidance for industry on Incorporation of Physical-Chemical Identifiers (PCID) into Solid Oral Dosage Form Drug Products for Anticounterfeiting in July 2009 and published a final version in October 2011.  Briefly, this guidance addresses the addition of a non-active ingredient to solid oral dosage forms that may be used to verify the authenticity of the product.  PCIDs are analogous to the placement of inactive “taggits” in explosives that permit identification of the source of manufacture and becomes a useful tool in criminal investigations.  Few changes were made to the draft guidance based on industry comments, modifications include:

  • The addition of section VI, addressing toxicology / safety concerns where PCIDs are added to either packaging or container labeling. In this section,  FDA addresses the possibility for toxicological concerns where the PCID may migrate from the location where it was placed into the product itself.  FDA strongly encourages manufacturers to speak to the relevant review center to address these concerns. 
  • The final document does not require specifications for the PCID whereas the draft document did require specifications.
  • FDA is also not requiring that PCIDs be included in the component labeling unless there is a change in the identifying characteristic of the dosage form such as color.  This is important because it constitutes one means of covert anti-counterfeiting protection.  

To view or download the guidance, click here

To view or download the Rx-360 summary of the guidance, click here


Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances Minimize

The IMB published a “Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances” on October 5, 2011. The link below will take you to the document.  This is not a draft document for comment, but appears to be a finalized guidance. 


Most of the document focuses on cold chain management but it also addresses “controlled temperature” storage and shipment.  The guidance has a section on Management of Temperature Excursion that states “All excursions should be promptly and thoroughly investigated” and that the Responsible Person should be notified immediately.  Those involved in stability and packaging / distribution are encouraged to read the entire 20 page document.  Relevant requirements include but are not limited to the following:

·         Products should be stored under labeled conditions

·         Transport qualification should include actual shipment of materials to the   furthest location and not rely exclusively on laboratory studies

·         Temperatures in a refrigerated transport vehicle should be controlled and monitored “with recording probes or individual temperature monitoring devices”

·         Returned cold chain products may be returned to saleable stock if there is “no reasonable possibility that the cold-chain has been compromised”

·         MKT is relevant only for controlled room temperature conditions, it is not appropriate for use with products that require controlled low temperature storage

·         Calibration of probes used in temperature monitoring should be performed at 3 temperatures across the range at which the probe will be used



To view or download the IMB Transportation Guidance, click here

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


US Proposed Legislation S.1584, Drug Safety and Accountability Act of 2011 Minimize

Senator Bennet introduced S.1584, “Drug Safety and Accountability Act of 2011”  on September 20, 2011.  A recent Rx-360 flash report provided a brief overview of the draft legislation.  This slide deck summarizes relevant features of the bill.  This bill would give FDA the express authority that they have requested in several areas:  recall authority, authority to conduct foreign GMP inspections and clear unambiguous identification of the site(s) that are subject to inspection.  We will continue to track and report on this and other relevant legislative proposals as they make their way through the US Congress.

To view or download the draft legilsation, click here 

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

To view all previous Rx-360 Summaries, click here


FDA Conducts Preliminary Review of Agency’s Minimize

This review is a novel approach to help FDA identify vulnerabilities in the U.S. drug supply chain and provide some insight into the schemes, types of products, and supply chain participants involved to help FDA prioritize risk management activities and develop a more proactive regulatory approach to combat the problem. The US has one of the safest drug distribution systems in the world and FDA notes that drug counterfeiting is relatively rare in the US.   However, FDA is still concerned that the drug supply is increasingly vulnerable to diversion of legitimate drugs (drugs illegally circulated outside the legal distribution system ie stolen or sold illegally) and concerned about the influx of counterfeit drugs- as both present significant risks to public health. 

FDA collected information from judicial diversion and counterfeiting cases investigated by the Agency’s Office of Criminal Investigations (OCI) from 2003-2008 and the data was reviewed by Center for Drug Evaluation and Research (CDER).  FDA highlights three examples of criminal drug schemes investigated by OCI and evaluated types of drug products and identified the Trade of the suspects which included Brokers, Doctors, Importers, Manufacturers, Pharmacists, Pharmacies, Repackagers, Sales Representatives, Wholesalers, Practitioners even Consumer/Patients, Truck driver and Shippers. 
The 3 schemes included: 

1. Counterfeit Scheme - A licensed pharmacist ordered counterfeit drugs from China and the counterfeits products were discovered and stopped at the border from entering the U.S. supply

2. Wholesale Distributor Diversion Scheme- Drugs were purchased by the secondary wholesalers or stolen from patients and/or manufacturers and sold to drug wholesalers and pharmacies in various states
3. Pharmacy and Pharmacist Diversion Scheme - Drug company Sales Representatives sold drug samples to a pharmacy, which then broke open the individual sample packages and sold them to patients at the retail price
The report looked at the various categories of “trade” organizations with which counterfeiting or diversion suspects were associated.  Wholesalers (25%), pharmacists (13%) and doctors (9%) were the three highest categories behind “other” (31%).  The findings noted solid oral dosage forms (tablet or capsule) were the most common products targeted. The top five brand products identified in the counterfeit and diversion cases reviewed were Zyprexa, Viagra, Lipitor,  Zoloft and  Risperdal. This is an initial evaluation of the OCI activities and is not meant to be predictive of future criminal activities in these areas.  FDA indicates they will “conduct further analysis and report as appropriate.” 
To view or download the FDA report, click here

WHO Annex 9: Model Guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products Minimize

The WHO Expert Committee on Specifications for Pharmaceutical Preparations recently published the Technical Report Series 961.  Fifteen annexes were included as part of the report including a new Annex 9, Model Guidance for Storage and Transport of Time- and Temperature- Sensitive Pharmaceutical Products.  This Annex addresses clearance thru customs, attributes of storage buildings including security, fire protection and the power supply.  Section 4 addresses the specific requirements of temperature controlled storage and Section 6 addresses transport and delivery within several detailed subsections.  Also covered are documentation requirements, personnel training and the requirements for shipping containers.  While the larger report may also be of interest to readers, we focused our analysis on Annex 9 addressing transport and storage of pharmaceutical products.


Model Guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products go to:




Annex 9 begins on page 324 of this report.



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

To see previous Rx-360 summaries,
click here


Rx-360 Summary FDA Bar Code Labeling Minimize

FDA published a revised Guidance for industry:  Bar Code Label Requirements---Questions and Answers, on August 11, 2011.  This revision amends the response to Question 12 of the October 2006 guidance and allows vaccine manufacturers to use “alternative coding technologies” to linear bar code technology.  FDA feels this is necessary based on the mandatory recordkeeping requirements associated with administration of childhood vaccines.  Administration generally occurs in a physician office or clinical that may have limited administrative support to record the necessary data for each administration and use of alternative coding technologies may facilitate collection and recording of this information.  


To view or download the FDA's Q&A, click here
To view or download the FDA's Update Q&A, 
click here


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

To see previous Rx-360 summaries,
click here


USP <1079> Storage and Distribution Practices Minimize

The revision to USP chapter <1079> is extensive and addresses storage and transport of drug products “from manufacturer to end user.”   The USP chapter was first published in 2003.   This represents a second attempt at revision of the chapter with the revision proposed in January – February 2010 having been canceled. 

The proposed revision of the entire chapter is prompted by the growing complexity and globalization of finished product supply chains and the need for controls to be in place along each segment of the distribution chain.   

The importance of maintaining temperature and other environmental controls becomes more important with global distribution.   Companies may submit comments on this chapter revision to USP by September 30, 2011. 

To view or download the USP <1079> proposed revision, click here
To view or download the Rx-360 Summary,
click here

To see previous Rx-360 summaries,
click here



PIC/S Questions & Answers document regarding Distribution Activities Minimize

This list of Questions and Answers were agreed to by inspectors of the PIC/S Expert Circle of APIs at a meeting in Dublin, Ireland in May 2010. The document was published on 24-March-2011, and is intended to provide guidance to inspectors when inspecting areas relating to two topics: (a) Supply Chain & Distribution and (b) Repackaging & Relabelling Operations, references to the PIC/S Guide to GMP Part II are provided with answers, where appropriate.

The following are highlights from the document that Rx-360 wants to bring to the attention of a wider audience. 



Rx-360 has always been a proponent of supply chain transparency and the PIC/S document also stress the importance of transparency in the following Questions and Answers:

Q11. Is it acceptable to hide the origin of an API after repackaging / relabeling operations?

A11. No. (refer to Question 8 also). According to sections 17.60 and 17.61, the name of the original API manufacturer and batch number should be provided. Furthermore, Certificate of Analysis from the original API manufacturer mentioning its contact details should be transferred to the customer as stated in sections 11.43 and 11.44.   

--- || --  

Q8. There is no definition included in PIC/S GMP guidelines regarding relabeling and repackaging activities. What is PIC/S APIs experts’ view on that matter?


 A8. Relabelling of containers is the placing of additional labels onto containers which does not impact, obliterate or destroy the manufacturer’s original label, in order to maintain traceability of the supply chain. Any act of relabeling that impacts upon the manufacturer’s original label and hence traceability, may be considered as adulteration or an attempt of falsification.  

--- || --  

Q4. How does the finished product manufacturer assure its knowledge about and the integrity of the whole API supply chain?

A4. The whole API supply chain should be established, known and documented by the finished product manufacturer in collaboration with the API manufacturer as part of its supplier selection and approval process…  

--- || -- 

 Within the Answer to Question 1, PIC/S states that financial records should be used to validate the authenticity of the supply chain during inspections; within the Answer to Question 2, PIC/S defines what is the original API manufacturer that the finished product manufacturer must trace their supply change back to; and within the Answer to Question 4, PIC/S states that the finished product manufacturer should establish and document the entire API supply Chain.

The PIC/S document provides very clear expectations regarding distribution activities of Active Pharmaceutical Ingredients (APIs) and allows industry to prepare to meet and demonstrate compliance to these expectations during future inspections.

To view or download the PIC/S document, click here



FDA Collaborates with Foreign Counterparts Minimize

For Immediate Release: August 2, 2011
Media Inquiries: Shelly Burgess, 301-796-4571,
[email protected]

Consumer Inquiries: 888-INFO-FDA
FDA, international counterparts report progress on drug inspection collaboration

The U.S. Food and Drug Administration, together with its European and Australian counterparts, today released two reports detailing the results of pilot programs focused on increasing international regulatory collaboration among the agencies so that drug quality and safety can be enhanced globally.  

The report on the Good Clinical Practice (GCP) initiative details the success of information-sharing and collaboration on inspections relating to clinical trials. Under the GCP pilot program, the FDA and the European Medicines Agency (EMA) exchanged more than 250 documents relating to 54 different drug products and, in conjunction with the GCP inspectors of the EU member states, organized 13 collaborative inspections of clinical trials. This lays the foundation for a more efficient use of limited resources, improved inspectional coverage, and better understanding of each agency’s inspection procedures. It demonstrates how the agencies can work together to improve human subject protection and better ensure the integrity of data submitted as the basis for drug approvals. 

The report on the Active Pharmaceutical Ingredients initiative details the success of information-sharing among the FDA, Australia’s Therapeutic Goods Administration and for Europe, the EMA, France, Germany, Ireland, Italy, the United Kingdom and European Directorate for the Quality of Medicines & Healthcare (EDQM). Over the course of the 24 month pilot phase, the participants shared their surveillance lists and found 97 sites common to all three regions, resulting in the exchange of nearly 100 inspection reports and in nine collaborative inspections. The FDA used these reports to inform decisions, such as whether to postpone or expedite its own inspection. The FDA also prohibited imports into the U.S. 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.

“It is imperative that FDA work closely with its counterparts in order to ensure the safety and quality of products and the integrity of clinical trials. We cannot do it alone,” said Deborah M. Autor, FDA deputy commissioner for Global Regulatory Operations and Policy. “We are grateful to our European and Australian colleagues for their willingness to partner with us in these pilot programs. The pilots are important stepping stones toward further global regulatory collaboration.”

These pilot programs are part of the FDA’s global strategy to ensure the safety and quality of imported products. The new strategy builds on efforts that are currently underway at the FDA. The agency increased the number of foreign drug manufacturing inspections by 27 percent between 2007 and 2009 and has opened several international offices in key locations such as China and India. The FDA has been an active contributor in the effort to harmonize certain aspects of drug regulation via the International Conference on Harmonization, and the agency recently joined the Pharmaceutical Inspection Cooperation/Scheme, an organization of drug manufacturing inspectorates from 39 countries.

In June, the FDA unveiled a new strategy to meet the challenges posed by rapidly rising imports of FDA-regulated products and a complex global supply chain in a report called the "Pathway to Global Product Safety and Quality." The FDA report calls for the agency to transform the way it conducts business, to build upon its ongoing collaborations with its regulatory partners around the world, and to act globally in order to promote and protect the health of U.S. consumers. In the report, the FDA says that it will partner with its counterparts worldwide to create global coalitions of regulators focused on ensuring and improving global product safety and quality. FDA looks forward to working with its counterparts on this important effort.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products. 

For more information:

Report on the Pilot EMA-FDA GCP Initiative, September 2009 – March 2011

Final Report on the International API inspection Pilot Programme, May 2011

Frequently Asked Questions and Answers for the Report on the Pilot EMA-FDA GCP Initiative,
September 2009 – March 2011


EU Draft GDP Guidance Minimize

The European Commission recently published a draft revision to the Guidelines on Good Distribution Practices (GDP).  Public consultation on this draft will close on December 31, 2011, and the revised guideline will become effective six months after publication.  Regulators have determined that the current GDP guidelines, published in 1994, are no longer adequate considering the expansion of the global supply and distribution chains.  The 1994 document is four pages long and the proposed revision is 32 pages long and provides more granularity on all topics.  The draft revision covers a broad range of topics from Quality Systems through Contract Operations, Requirements for Brokers and specifics of Operation and Transportation.  We encourage companies to evaluate the draft and consider providing comments either as individual companies or through trade organizations.


To View or Download the Draft EU GDPs, Click Here

To View or Download the Rx-360 Summary, Click Here


FDA Modifies Prescription Drug Marketing Act Minimize

On 14 July, the FDA issued a Federal Register notice proposing removal of a rule that has been in effect only seven days since it was finalized in 1999, having spent most of its lifetime in various stages of legal challenge by industry.  (See: Removal of Certain Requirements Related to the Prescription Drug Marketing Act.)   21CFR 203.50(a) requires an unauthorized distributor to provide a pedigree to the purchaser “a statement identifying each prior sale, purchase, or trade of such drug” beginning with the manufacturer.  The documentation must also include specified information about the drug and each prior “sale, purchase or trade.”  Until the rule is formally removed, FDA will show discretion in enforcement of this requirement.  The Federal Register announcement provides a lengthy history of this rule and the various legal challenges.


To View or Download the Federal Register Notice, Click Here

To View or Download the Rx-360 Summary, Click Here


New Saudi Arabian GMPs Minimize

Saudi Arabia recently published version 2.0 of their GMPs, to be effective July 26, 2011.  This replaces version 1.0 published in June 2005.  The GMPs address all aspects of manufacture and testing, though only those items which are supply chain specific are addressed in the accompanying slide deck.  Scope of the document includes investigational medicinal products, commercial product, raw materials, intermediates and contract manufacture.  Companies are encouraged to evaluate the entire GMP guide in addition to the supply chain aspects which we highlight herein.  While the format and organization is similar to the EU GMPs and to the PIC/S GMPs,  those areas which are different are highlighted in the document.   



To View or Download the Rx-360 Summary, Click Here

 To View or Download the Saudi Arabian GMPs, Click Here


EU Batch Certification Minimize

On June 1, 2011 the EMA finalized Internationally harmonised requirements for batch certificationThis describes the content and format of the Batch Certification required to be issued by the manufacturer in the exporting country.  This is relevant to those countries that have mutual recognition agreements with the EU:  Australia, Canada, Israel, Japan, New Zealand and Switzerland.  The short document identifies the 17 requirements and provides explanatory notes and a glossary.  The changes in this revision include the addition of a glossary and adoption by the GMDP IWG.  As reported in the ECA Newsletter (7/13/2011) this is now added to Part III of the EU GMP Guide along with the format and content instructions for the Site Master File.


To View or Download Announcement, Click Here



EU Falsified Medicines Directive Minimize
On July 1, 2011 the Official Journal of the European Union published the finalized text of the so-called “Falsified Medicines Directive.”  A copy can be accessed by clicking here

The next step in the process is for the EU member states to incorporate the content and requirements into their national laws.  This step must be completed by 02-January-2013 although certain safety features will be implemented on a different time frame.

The summary provided in the slide deck previously published by Rx-360 contains a high level summary of the legislation which remains unchanged, and which can be viewed or downloaded by
clicking here.

Specific GMP and inspection features must be developed in the intervening 18 months to permit full implementation of the legislation.  Among the aspects of the legislation that require additional explanation and clarification are:
  • Qualified Person (QP) declaration that API manufacture complies with GMP
  • Process by which the API supply chain traceability is to be established and documented
  • Criteria for identifying non-EU countries that may import API into the EU
  • Identification of appropriate GMP standards for production of excipients
  • An implementing act identifying GMP standards for APIs



US FDA's Pathway to Global Product Safety and Quality Minimize

In their recent report, Pathway to Global Product Safety and Quality, FDA indicates that they must  transform their operations in light of the global manufacture of the product and components that they regulate.  Previously FDA functioned as a domestic agency but now must expand their horizons and partnerships with other regulatory agencies to effectively protect the public health and safety of citizens of the US.  The report provides a detailed history and reasons for the move from domestic manufacture and production to the global nature of the products that they regulate and how FDA will respond to these changes.  The  FDA states that the transformation from a purely domestic agency to one operating in cooperation with global regulators  will be built on “four core building blocks”:

  • FDA will work to build global coalitions of regulators
  • Within these coalitions, FDA will develop information sharing systems and networks where real-time information may be available
  • FDA will continue to enhance intelligence gathering with a focus on risk analytics and modernized IT capabilities
  • FDA will work to leverage the capabilities of government, industry, public and private third parties as they allocate their own resources in a risk based manner

To download / view the FDA Global Pathway Document, click here

To download / view the Rx-360 Summary of FDA's Global Pathway Document, click here


Turkish GMPs and Audit Standards Minimize

The Turkish GMP/GDP inspectorate has become far more active in the past year as pharmaceutical companies view Turkey as an important country for their expansion efforts.  The GMPs included in this report appear to generally closely mirror the EMA and PIC/S GMPs and covers all aspects of GMPs including production of  clinical trial medicinal products.  The GMP / GDP checklist included here also covers all aspects of GMP/GDP and should prove valuable to companies who are anticipating inspections from Turkish authorities.  Both documents are lengthy and cover items in addition to supply chain oversight,  raw materials and component purchase and testing.  Companies should find this a valuable addition in preparation for medicinal product inspection conducted by Turkey. 


To download / view the Turkish GMPs/GDPs, click here

To download / view the Turkish GMP/GDP audit checklist, click here 

To download / view the Rx-360 Summary of Supply Chain Items
covered Turkish GMPs/GDPs, 
click here



IPEC-Americas Minimize

IPEC-Americas Releases Good Distribution Practices Audit Guide for North American Distribution of Pharmaceutical Excipients.


The IPEC-Americas GDP Audit Guide (produced by the IPEC-Americas GMP Committee on January 2011) is designed to be used by distributors, brokers, and traders of excipients primarily in North America, but can also be used as a resource for auditing distributors globally.  It applies to all steps in the supply chain, beginning where the excipient is outside the control of the original manufacturer’s material management system.  The Audit Guide can be used as an audit checklist, or as a tool to assist with determination of the focus and scope of an audit.  The IPEC-Americas Audit Guide is also designed to be used with IPEC’s Good Distribution Practices Guide for Pharmaceutical Excipients (2006).  

The IPEC-Americas Audit Guide begins with a Matrix of Applicability.  This Matrix defines GDP activities that may apply to the particular distribution operation being assessed.  Examples of activities identified include transportation of packed excipients, transportation of bulk excipients, and relabelling.  The Matrix of Applicability then defines the applicability of thirteen (13) audit sections (complaints, recalls, quality management) associated with each type of GDP activity.  The applicability is identified by a Greek letter. 

By identifying both the particular distribution operation being assessed and its associated applicability, the auditor can then create a customized audit checklist by selecting from the numerous open-ended questions covering over 95 categories contained within the thirteen (13) quality audit sections.

Additional information, including a pdf copy of the Audit Guide, is located on the IPEC-Americas website

IPEC Americas is comprised of members representing Excipient Users, Makers, and Distributors .  Visit
www.ipecamericas.org to learn more.


US HR1483: Proposed Drug Safety Enhancement Act of 2011 Minimize


The Drug Safety Enhancement Act of 2011 has been introduced by Congressman Dingell and others as HR1483.  It includes many of the features in previous draft drug legislation as well as some features similar to the food safety legislation that was passed by Congress last year.  Features that would be required by the legislation include, but are not limited to:

  • Establishment registration for excipient manufacturers
  • Failure to have an effective quality system would deem the drug to be “adulterated”.  Such an effective quality system would include features of:
    • Management Responsibility
    • Quality Responsibility whereby the Quality unit would be “…an internal, independent unit…”
    • Risk ManagementSupply Chain Management
  • Inspections for drug product and API shall occur once every two years or once every four years if compliance history indicates.  
    • Additional sources of funding for foreign inspection activities
    • Inspections of excipient manufacturers may occur
    • Inspection of foreign sites shall be on par with inspection of domestic US manufacturing sites
  • Recall authority
  • Authority to detain and destroy product at the US border
  • Increased criminal and civil penalties
  • Drug / web site labeling with country of origin for active ingredient and country where drug product was manufactured
  • Protection for whistleblowers

To view or download US HR1483,  click here

To view or download Rx-360 Summary of US HR1483, click here



US Importation of Wood Packaging Minimize

On December 2, 2010, the Department of Agriculture published a proposed rule in the Federal Register to amend 7 CFR 319.40-3 regarding the importation of wooden packaging material from Canada.  This would impact the pharmaceutical industry and its suppliers because it applies to wooden pallets and wooden crating for equipment and other supplies.   Wooden packaging material imported  from countries other than Canada must meet International Standards for Phytosanitary Measures (ISPM) 15 that  requires wooden packaging materials be subject to either heat treatment or fumigation with methyl bromide and must be marked appropriately.  The current rule allows for such materials to be imported from Canada under a general permit that guarantees the wood was harvested in Canada and has not been moved outside the country.  The lower burden for these materials assumes that the same forest pests exist both in the United States and Canada.  Revised risk assessments have identified forest pests that are unique to Canada, and this revised rule would prevent their introduction, or re-introduction in some cases, into the United States.  Thus, if finalized as written, this rule would require that wooden packaging materials imported from Canada meet the same requirements as these materials sourced from all other countries.


To view or download the announcement, click here


Rx-360 Summary of Counterfeit Pharmaceutical Inter-Agency Working Group Report to the Vice President of the United States and to Congress Minimize

A US government inter-agency working group finalized a report dated March 2011 addressing the issue of counterfeit pharmaceuticals.  The report was issued to the Vice President of the United States and to Congress and provides a summary of US law enforcement actions, international law enforcement actions, cooperative efforts focused on illegal internet sales, and ways to improve public awareness of the issues in both the US and internationally and other related issues.   The report recommends legislation to address the range of challenges posed by counterfeit drugs including: 

  • Importers and manufacturers should notify FDA when they identify counterfeit drugs,
  • Pharmaceuticals and related products should be subject to a track-and-trace system,
  • Congress should increase the maximum fines and penalties for counterfeit drug offenses

To view or download the US Vice President's Report to Congress, click here

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


FDA’s final Guidance for Industry, Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products Minimize

Rx-360 Summary of FDA’s final Guidance for Industry, Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products

FDA has finalized their Guidance for Industry, Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products (MNPs).  The guidance applies to drugs and therapeutic biologic products regulated by CDER and “manufacturers of materials and components used in those products.” It does not appear to apply to CBER regulated medical products such as vaccines and blood / blood products or medical devices regulated by CDRH.  No explanation is provided for exclusion of these product types.  Because it applies to manufacturers of raw materials and components used in manufacture of drugs and therapeutic biologic products,  “FDA strongly recommends that drug product manufacturers show this guidance to all suppliers and contractors associated with the manufacture of MNPs and discuss the guidance with them to stimulate planning to avoid or mitigate disruptions in supply.”  The guidance provides CDER’s current thoughts on how the regulated industry should prepare for disasters that may impact the availability of medically necessary products as defined in MAPP 6003.1.  The guidance describes development and implementation of a plan and communication with the agency when the plan is activated and deactivated.  The guidance also mentions enforcement flexibility that may be available in specific instances.  Of particular relevance for both manufacturers and their suppliers is the expectation to share this information with all suppliers and contract sites as articulated above.


To view or download the FDA Guidance, click here

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


FDA has published a draft Guidance for Industry, Non-Penicillin Beta-Lactam Risk Assessment Minimize

FDA has published a draft Guidance for Industry, Non-Penicillin Beta-Lactam Risk Assessment:  A CGMP Framework.  Existing GMPs require that “Air handling systems for the manufacture processing and packing of penicillin shall be completely separate from those for other drug products for human use” (21 CFR 211.46(d)).  ICHQ7, GMPs for API manufacture, require “Dedicated production areas, which can include facilities, air handling equipment and/or process equipment should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins” (ICHQ7 4.40).  FDA now considers that sensitizing non-penicillin beta-lactams should be manufactured and controlled the same as penicillin is manufactured and controlled and they provide their proposals and justification for segregation in this guidance.  The guidance applies to manufacturers of APIs and dosage forms, packagers and re-packagers.  Pharmacy compounding is regulated by the individual states, but FDA indicates that they may “find the information useful.”  

This guidance document is driven by health concerns because the class of molecules is highly sensitizing.  The five classes of beta-lactam antibiotics and their intermediates and derivatives act as sensitizing agents in some members of the population and trigger allergic responses that can be serious and life-threatening.  The exposure dose that results in an allergic reaction is extremely low, difficult to define and difficult to detect..  A suitable animal model or in vitro receptor model does not exist that will accurately predict human sensitivity.  Individuals who are sensitive to one beta-lactam may frequently show sensitivity to another class of beta-lactam.  To address this potential health risk, FDA is proposing to apply the GMPs for the management of penicillin manufacturing facilities to all five classes of beta-lactam antibiotics.  Further, they are suggesting that each class be manufactured in areas separate from where other drugs, including other beta-lactams, are manufactured.  Manufacture of different beta-lactams within the same class “would generally not mandate separate facilities and air handling systems, and could permit production campaigning and cleaning as sufficient control.”


To View / Download Draft of FDA Guidance, Click Here

To View / Download Rx-360 Summary of Draft FDA Guidance,
Click Here


Rx-360 Summary of EU Counterfeit Medicines to Directive Minimize

On February 16, 2011, the European Parliament adopted the amendments on Counterfeit Medicines to Directive EC 2001/83/EC.  Wording for the official text is not yet finalized and additional details regarding specific requirements remain to be resolved.  The European Council must formally approve the final wording and  the national regions will have 24 months to incorporate these features into their legislation.   Please note that the text of the final document has not published and Rx-360  prepared this slide deck summary based on what we anticipate will be included in the final version. 

These amendments represent a significant move to protect the public from counterfeit medicines.  Four key features of the Directive are as follows:

  • Introduction of a Europe wide system of serial numbers to be used to verify drug authenticity at the pharmacy level.  This could be implemented in a way that would allow pharmacists to determine whether a drug had been recalled or previously dispensed and thus intercept possible counterfeit medicines before they reach the public
  • Internet pharmacies would be subject to increased regulation and registration requirements.  In addition, the public would be warned of the potential dangers of purchasing drugs from internet site
  • APIs will be subject to more strict rules upon import into the EU and the holder of the manufacturing authorization must ensure that APIs and excipients are authentic and comply with good manufacturing practices. 
  • Counterfeiting of medicines is recognized as a crime  and  Member states need to ensure that penalties developed for this crime are “effective, proportionate and dissuasive”. 

To view or download Rx-360 Summary, click here

  To view or download EC Directive,  click here



EMA's draft Qualified Person's (QP) Template and associated Q&A Minimize

The EMA recently published two documents for consultation: (i) a template for the QP declaration concerning GMP compliance of active substances and (ii) an associated Question & Answer document.  This represents a continued focus of regulators on the supply chain, particularly for active substances used as starting materials.  The purpose of the QP declaration is to:

  • Verify GMP compliance of parties in the supply chain for active substances
  • Ensure activities are conducted in agreement with the regulatory submission
  • Understand and control the supply chain for active substances
  • Demonstrate that each batch of active substance has been sourced thru the appropriate supply chain

The EMA indicates that this imposes no new requirements and that understanding and controlling the supply chain for active substance is already an expectation of GMP compliance.  The GMP compliance of the active substance manufacturer is to be established by a direct audit, although audit by a 3rd party is an acceptable alternative.  GMP certificates do not substitute for a direct audit by the drug product manufacturer, but can constitute supporting information.  Verification of the supply chain begins with critical raw materials that are used in manufacture of the active substance and includes operations post active substance manufacture such as micronization.  The verification documentation is to be available for inspection by the competent authorities.  Readers are strongly encouraged to read the original documents because the level of detail provided in the documents is impossible to capture in a slide deck summary.


To view or download Rx-360 Summary and EMA documents, click here


EMA Road map 2015: The Agency’s Contribution to Science, Medicines, Health Minimize

In January 2011, the EMA published their “Road map to 2015”.  This is a continuation of a practice that EMA began with the publication of their first roadmap in 2005: “Road map to 2010”. The 2011 document was published for public consultation in early 2010 and this final version represents the Agency’s vision for the regulation of both human and veterinary drugs, identification of the specific drivers and initiatives they plan to undertake, as well as the challenges faced by the agency.  Of particular importance in this document is the recognition of the challenges posed by globalization, and the importance of coordination with EU legislation being developed to address falsified medicines.  The document addresses many facets of EMA challenges and activities proposed thru 2015.  The report identifies the following drivers for these activities:

  • Need to ensure efficient operation of the Agency’s core business
  • Addressing ongoing public health needs including demographic changes, emerging public health threats, antimicrobial resistance and rapid development of new technologies
  • Evaluating new and emerging science which may address unmet medical needs
  • Ensuring that the model for regulating medicines remains current and effective
  • Protection of public safety
  • Addressing the need for more openness and transparency and
  • Addressing the impacts of globalization

Regarding the last bullet point, EMA reports they have growing concerns regarding “…the increasing manufacture of active pharmaceutical ingredients (APIs) outside the EU, and in particular the potential for substandard material to enter the supply chain.” 


To view or download the EMA Road Map 2015, click here


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


Revision to Annex 11 of the EU GMP Guide, Computerized Systems Minimize

The EMA has published the first revision to Annex 11 of the EU GMP Guide, Computerized Systems.  The effective date for this Annex is June 30, 2011.  The increased use of computer systems and their complexity prompted a revision to this Annex.  Of particular importance to Rx-360 member companies is a new section on “Suppliers and Service Providers” that addresses how third party activities such as development, installation and validation of such systems should be controlled and documented.  This includes making audit information regarding these suppliers and software developers available to inspectors upon request.  In addition, the level of detail and requirements within the Annex have been substantially expanded from the previous version and include a life cycle approach to management of computer systems that is supported by risk management.


To view / download Rx-360 Summary, click here


To view / download revised Annex 11, click here


Rx-360 Summary of EU draft revisions to Chapter 5 (Production) of the GMP Guide Minimize

The European Union has published draft revisions to Chapter 5 (Production) of the GMP Guide. The proposed revisions reflect a focus on control of raw materials and changes have been made to paragraphs 25, 26, 27 and 31, with emphasis on control of starting materials. Note that by definition, starting materials are “any substance used in the production of a medicinal product, but excluding packaging materials.” The proposed revisions include:

  • New section 5.26 addresses selection / control of starting materials, new requirements include: 

o   Vendor selection should include evaluation of supply chain risks
o   This section also addresses critical packaging materials which along with starting materials, should have procedures which govern their assessment, purchase and acceptance.
o   The approval of suppliers should be controlled by QC and production (we will likely comment on this item and request that it be controlled by the “Quality Unit”)
o   Suppliers of APIs and certain excipients should be periodically audited to ensure they conform with GMPs
o   Audit reports of these vendors should be available upon request for review by inspectors
  • New section 5.31. All new text that addresses testing of starting materials that is subcontracted and a NOTE section indicates that this also applies to packaging materials.  

o   An agreement should be written to describe responsibilities
o   The finished product manufacturer should audit the laboratory at “appropriate intervals”
o   The CoA should be signed by a person with appropriate qualifications and experience
o   Full analyses on three different batches should be performed prior to reduced in-house testing.  The finished product manufacturer should also perform full testing initially.    
Comments on the draft revisions, if companies are interested, are due no later than February 28, 2011.

To view or download the EU Draft Revisions, click here


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



2009 © Rx-360