Friday, October 31, 2014
2013 Summary Index Minimize

 

Report
Number

Description Date
Issued
424
FDA announces moves to avert drug shortages

01-Nov-13
416
Read Rx-360's Summary of FDA's Supply Chain Security Program

28-Aug-13
415
Rx-360 Summary of ICHQ3D, Guideline for Elemental Impurities; Step 2b
 
07-Aug-13
414
Rx-360 Summary of the US FDA's implementation of Title VII of the FDASIA (Food and Drug Administration Safety and Innovation Act) 

 06-Aug-13
412
Rx-360 Summary of Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products

 
30-Jul-13
411

 

Rx-360 Summary of EU’s Falsified Medicines Directive Rule (Article 46b 2011/62/EU)

 

30-Jul-13
409


Rx-360 Summary of the US Congressional Research Services Pharmaceutical Supply Chain Security Report

 

25-Jul-13
408


Rx-360 Summary of the US FDA's Recently Published a New Guidance for Industry, Heparin for Drug and Medical Device Use

 

16-Jul-13
407


Rx-360 Summary of the US FDA's implementation of Title VII of the FDASIA (Food and Drug Administration Safety and Innovation Act)

 

02-Jul-13
406


India's List of API Manufacturers Confirmed for Export to EU

 

15-Jul-13
405


FDA shuts down over 1,600 online pharmacies

 

28-Jun-13
404


At the Last-Minute, EU Says US Clear to Export APIs Under Falsified Medicines Directive

 

22-Jun-13
401
EMA has issued Q&As addressing GMP requirements for active substances

02-Jun-13
400
Rx-360 Summary of Health Canada New API Regulations

02-Jun-13
398
USP Elemental Impurities Update

28-May-13
397
Rx-360 Summary of FDA Draft Guidance on Contract Manufacturing Arrangements for Drugs: Quality Agreements

28-May-13
396
Rx-360 Summary of the United Nations Transnational Organized Crime in East Asia and the Pacific

10-May-13
395
Rx-360 Summary of the FreightWatch 2013 Global Cargo Theft Threat Assessment

 
10-May-13
391

 

Free Rx-360 Summary Chart of the European Commission's Falsified Medicines Directive

 

01-May-13
390

 

Rx-360 Summary of the US House of Representatives conducted a hearing entitled Securing Our Nation’s Prescription Drug Supply Chain

 

29-Apr-13
389


Rx-360 Summary of Guideline on the Use of Porcine Trypsin Used in the Manufacture of Human Biological Medicinal Products

 

27-Apr-13
386


Rx-360 Summary of Importation of Active Substances For Medicinal Products for Human Use, Questions and Answers, Version 4.1

 

22-Apr-13
385


Rx-360 Summary of New Saudi FDA Guidance for the Storage and Transport of Time and Temperature Sensitive Pharmaceutical Products

 

10-Apr-13
382
Rx-360 Summary of EC Importation of Active Substances for Medicinal Products for Human Use, Questions and Answers

07-Apr-13
380
Rx-360 Summary of US FDA Draft Glass Syringe Guidance

05-Apr-13
377
Rx-360 Summary of EMA Draft Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities

30-Mar-13
376
Rx-360 Summary of the China SFDA Published a Good Supply Practice Guidance

29-Mar-13
374
EMA Released Revisions to 4 GMP Chapters and is Seeking Public Comment

22-Mar-13
372
Read the Rx-360 Summary of the New EC GDPs

20-Mar-13
371
Notification on Matters Related to the Implementation of Electronic Monitoring of Imported Drugs

12-Mar-13
367
Rx-360 Summary of IOM Report: Countering the Problem of Falsified and Substandard Drugs

26-Feb-13
366

 

Read the Rx-360 Summaries of 3 Documents the EC Issued for Public Consultation

20-Feb-13
365
Rx-360 Summary of FDA Drug Shortages Task Force and Strategic Plan – Federal Register Notice

12-Feb-13
362

 

Rx-360 Summary of Indian Government Publishes Good Distribution Practices for Pharmaceuticals

 

05-Feb-13
361


ANVISA Requests Feedback On The Conditions For Granting The Certification Of GMP And GDP

 

04-Feb-13
352
Rx-360 Summary of U.S. FDA GMPs for Combination Products

22-Jan-13
351


Rx-360 Summary of the Indian “Guidelines on Recall and Rapid Alert System for Drugs (Including Biologicals & Vaccines)”

 

21-Jan-13
348
Brazil’s ANVISA Published Requirement for GMP Compliance by Manufacturers of Pharmaceutical Excipients

15-Jan-13

 

  

ICH Q3D Minimize

ICHQ3D, Guideline for Elemental Impurities

ICH posted the 79-page, step 2b version of ICHQ3D, Guideline for Elemental Impurities, on its website on August 5, 2013. 


Consultation comments are due to both FDA and EMA in December 2013.  The scope of the guideline includes chemically synthesized drugs, proteins and polypeptides made using cell culture expression systems and resulting conjugated proteins/polypeptides.  Elemental impurities in drug product may come from a variety of sources including those added during chemical synthesis, the presence of elemental impurities in raw materials, or those that result from contact with processing equipment.  

This guideline identifies elemental impurities that may have potential health/toxicology impact, establishes Permitted Daily Exposure (PDE) of those impurities and addresses controls necessary to maintain the impurities below the recommended PDE.  The document includes 7 sections (not including the Introduction and Scope) and four appendices as follows:

  • Safety Assessment of Potential Elemental Impurities (pages 2-4)
  • Element Classification (page 4)
  • Assessment and Control of Elemental impurities (pages 5-13)
  • Speciation (page 14)
  • Analytical Procedures (page 14)
  • Life-Cycle Management of the Control Strategy for Elemental Impurities
    (page 14)
  • Recommendations for Submission of Elemental Impurities Control Strategy (page 14)
  • Appendix 1:   Method for Establishing Exposure Limits (pages 20-22)
  • Appendix 2:  Established PDEs for Elemental Impurities (pages 23-25)
  • Appendix 3:  Individual Safety Assessments (pages 25-69)
  • Appendix 4:  Illustrative Example – Calculation Options for Converting PDEs to Concentrations (pages 69-79)

To view or download the ICH Q3D Document, click here

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

  

FDA announces moves to avert drug shortages Minimize
 

FDA announces moves to avert drug shortages

The FDA announced Thursday a strategic plan to both improve its response to drug shortages and also prevent shortages in the long term. Among the initiatives in the plan are: launching a new mobile app wherein users can access drug shortage information via smart phones; clarifying manufacturers' roles and responsibilities by encouraging them to engage in certain practices that will reduce the likelihood of a shortage; and updating the FDA's internal procedures for responding to early notifications of potential shortages. 

The FDA also proposed a new rule that would require drug manufacturers to notify the FDA at least six months in advance of a possible interruption in supply, or no later than five days after the interruption takes place. The agency would post a public noncompliance letter for drugmakers that fail to warn it about potential shortages. The new rule for notification would cover medically important prescription drugs, including certain biologics, and would also include decisions made by a firm to stop making a particular drug. 

Preventing drug and biological product shortages is a top priority for FDA. Working closely with manufacturers and other stakeholders, FDA was able to help prevent just under 200 drug and biological product shortages in 2011 and more than 280 such shortages in 2012, using tools such as:

  • Working with manufacturers to resolve manufacturing and quality issues contributing to short supply.
  • Expediting FDA inspections and reviews of submissions from manufacturers to prevent and/or alleviate shortages.
  • Identifying and working with manufacturers willing to initiate or increase production to cover expected gaps in supply.
  • Exercising enforcement discretion in appropriate circumstances, if this would not cause undue risk to patients.

 

To view or download the FDA Strategic Plan, click here

To view or download the Rx-360 Summary of the
FDA Strategic 
Plan, click here

 

To view or download the FDA Proposed Rule, click here

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

 

  

FDA Draft Guidance - Specification of Unique Facility Identifier (UFI) System for Drug Establishment Registration Minimize


FDA Draft Guidance - Specification of Unique Facility Identifier (UFI) System for Drug Establishment Registration

Rx-360 Issued: September 1, 2013

 

FDA has issued for comment a draft guidance on specification of the Unique Facility Identifier (UFI) System for registration of domestic and foreign drug Establishments. This guidance is intended solely to address the provisions in section 701 and 702 of Food and Drug Administration Safety and Innovation Act (FDASIA), which was signed into law in July 2012.

The guidance indicate that at this time, FDA’s preferred UFI for a drug establishment is the Data Universal Numbering System D-U-N-S (DUNS) number, assigned and managed by Dun and Bradstreet. Upon application, each business entity is assigned a distinct site-specific 9-digit DUNS number. The DUNS number is available free of charge to all drug establishments.

 

The FDA has been using the DUNS number as a registration number for drug establishments since implementation of electronic drug registration and listing.

 

  

FDA Secure Supply Chain Pilot Program Minimize


FDA Supply Chain Security Pilot Program

Rx-360 Issued: August 28, 2013.

 

On 20 August, the FDA announced the initiation of a pilot import program.  The Secure Supply Chain Pilot Program will launch in 2014 and, pending the outcome, it may become permanent.  The FDA is seeking 100 applicants for the pilot program with no more than 5 drug products per applicant.  This program is associated with Section 713 of FDASIA that 

“…authorizes FDA to require the submission of drug compliance information as a condition of granting admission to imported drugs…” including generation of regulations that may allow FDA to treat companies differently based on their compliance history and type of import.  This may permit expedited import of materials by and from highly compliant companies. The FDA announcement specifies 12 criteria that must be met by applicants to the pilot program (please see the Federal Register notice for details). 

To view or download the FDA Pilot Program, click here

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

 

  

ICHQ3D, Guideline for Elemental Impurities, Step 2b Minimize
 

ICHQ3D, Guideline for Elemental Impurities; Step 2b

Rx-360 Issued: August 7, 2013

ICH posted the 79-page, step 2b version of ICHQ3D, Guideline for Elemental Impurities, on its website on August 5, 2013.  The regulatory authorities in the ICH regions of US, Japan and the EU have not yet published it for consultation.  The Concept Paper and the Final Business Plan from 2009 are also included here. 

The scope of the guideline includes chemically synthesized drugs, proteins and polypeptides made using cell culture expression systems and resulting conjugated proteins/polypeptides.  Elemental impurities in drug product may come from a variety of sources including those added during chemical synthesis, the presence of elemental impurities in raw materials, or those that result from contact with processing equipment.  This guideline identifies elemental impurities that may have potential health/toxicology impact, establishes Permitted Daily Exposure (PDE) of those impurities and addresses controls necessary to maintain the impurities below the recommended PDE.  The document includes 7 sections (not including the Introduction and Scope) and four appendices as follows:

  • Safety Assessment of Potential Elemental Impurities (pages 2-4)
  • Element Classification (page 4
  • Assessment and Control of Elemental impurities (pages 5-13)
  • Speciation (page 14)
  • Analytical Procedures (page 14)
  • Life-Cycle Management of the Control Strategy for Elemental Impurities (page 14)
  • Recommendations for Submission of Elemental Impurities Control Strategy (page 14)
  • Appendix 1:   Method for Establishing Exposure Limits (pages 20-22)
  • Appendix 2:  Established PDEs for Elemental Impurities (pages 23-25)
  • Appendix 3:  Individual Safety Assessments (pages 25-69)
  • Appendix 4:  Illustrative Example – Calculation Options for Converting PDEs to Concentrations (pages 69-79)

 

To view or download the ICHQ3D Concept Paper, click here

To view or download the ICHQ3D Business Plan, click here

To view or download the ICHQ3D Step 2b Final Paper, click here

 

 

 

  

Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products Minimize
   

Guidance for Industry and FDA Staff:  Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products

Rx-360 Issued: July 30, 2013

The final guidance replaces draft guidance issued in April 2009 and is from CDRH, CDER and CBER and Office of Combination Products.  The guidance describes the information that is to be included in a marketing application where an injection device is used with a drug or biological product.  The guidance is divided into three sections:  Scientific and Technical Considerations, Content and Format Considerations, and Where Can I Find Additional Detail?  The second and third sections take up only 2 pages of the 29 page guidance, with the primary focus on scientific and technical aspects that should be addressed with the regulatory filing.  The Scientific and Technical Considerations includes but is not limited to:
  • Description: This includes identification of the “injector” indication for use, conditions of use and description of the drug/biologic.
  • Design Features: This includes comparison to existing “injectors”, engineering drawing and photos, dose setting and administration, graduation marks and fill lines, visual inspection of the drug or biological product, safety features, human factors design.
  • Materials used in the “injector” construction that should address possible leachables and extractables, adsorption of the drug/biological to surfaces, seal integrity and materials corrosion.
  • Performance testing general use considerations including biocompatibility, shelf life stability and expiry dating, environmental conditions for use, functional testing
  • Performance Testing with regard to the injector and drug/biological including:  dose accuracy, depth and route of injection, and special testing considerations (including extractables and leachables, adsorpables, container closure integrity and specific expiry dating)
  • Clinical Considerations in Performance Testing
  • Sterilization and Sterility Assurance
  • Cross contamination potential
  • Labeling

To view or download the guidance, click here

 

  

EU’s Falsified Medicines Directive rule (article 46b 2011/62/EU) Minimize

 

 

 

EU’s Falsified Medicines Directive  rule (article 46b 2011/62/EU)

Rx-360 Issued: July 27, 2013

On July 2nd 2013, the EU’s Falsified Medicines Directive rule (article 46b 2011/62/EU) requiring “written confirmations” to accompany each consignment of API imported into the EU for use in commercial Human Health drug product went into effect.

The Heads of Medicines Agencies (HMA) of the EU Member States have published a guideline to ensure a consistent approach is used for the release of APIs under this rule. The guideline provides a process map to follow in the case that an imported API consignment, which is not from countries listed under article 111b of te Directive, is not accompanied by a “written confirmation”.
 
The process asks for risk assessments to be provided to EMA (European Medicines Agency) and the European Commission by the national competent authority when no “written confirmation” is present and no waiver exists. This process is expected to be necessary only for a short interim period while these new rules are being implemented across the EU. The intention is to enable the EMA to monitor the situation, to coordinate inspections as needed and to keep the network informed.
 
To view or download the document, click here

 

  

Congressional Research Service Report on Pharmaceutical Supply Chain Security Minimize
 
Rx-360 Issued: July 25, 2013
 
Congressional Research Service report on pharmaceutical supply chain security
 
The Congressional Research Service (CRS) prepares reports for the Members and Committees of the US Congress. 

On July 12, 2013 they published a report titled “Pharmaceutical Supply Chain Security” that addressed the complexities in the global distribution supply chain for finished drug products. The complexities are well illustrated and described in Figure 1 (page 6) and a textbox (page 5) respectively. Between the time when a finished drug leaves the manufacturer it may pass through multiple primary and secondary wholesale distributors and often multiple dispensers before actually reaching the patient. This supply chain may also include a re-packager and third party logistics providers including temporary transport companies or warehouse providers. The complexity of the supply chain provides multiple opportunities for adulteration, drug diversion and counterfeiting. This report describes how Congress has moved to regulate the supply chain with details on the following:

  • Prescription Drug Marketing Act of 1987
  • Amendments to the Food and Drug Act in 2007
  • Food and Drug Administration Safety and Innovation Act of 2012
  • State Activities on Supply Chain Security
  • Actions taken by Professional and Industry Associations
  • Policy Decision Points under Consideration in the 113th Congress

To view or download the Congressional Research
Service Report,
click here

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

 

  

The FDA recently published a new Guidance for Industry, Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality Minimize
   

Rx-360 Issued: July 16, 2013

The FDA recently published a new Guidance for Industry, Heparin for Drug and Medical Device Use:  Monitoring Crude Heparin for Quality.  

This guidance is published as a final version. 

The Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), and Center for Devices and Radiological Health (CDRH) developed the guidance.

This guidance represents an ongoing focus on heparin arising out of the 2008 incidents involving adulteration of heparin with over-sulfated chondroitin sulfate (OSCS) which resulted in deaths in the US and several European countries.  The guidance highlights the importance of testing for contamination in crude heparin in addition to conducting tests that are identified in USP for testing of heparin sodium API.  The guidance provides context on the need for the guidance and the regulatory authority of FDA with regard to the sourcing and manufacture of heparin.  Section III describes five recommendations that drug or device manufacturers should take if they receive crude heparin that will be manufactured into drug product or that will be used in medical devices.  Establishing the species of origin and freedom from OSCS are the most critical elements expressed in the recommendations. 

To view or download the FDA Guidance, click here

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

 

  

FDA published two items in the Federal Register that are required to implement sections of Title VII of FDASIA Minimize
 

FDA published two items in the Federal Register that are required to implement sections of Title VII of FDASIA

Rx-360 Issues: July 15, 2013 

One year ago President Obama signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA), bipartisan legislation reauthorizing user fee programs for innovator drugs and medical devices and establishing two new user fee programs for generic drugs and biosimilar biological products.

 

 

FDASIA is helping FDA take important steps to address the challenges posed by an increasingly global drug supply chain in which nearly 40 percent of finished drugs are imported and nearly 80 percent of active ingredients come from overseas sources. FDA has been able to halt food and devices from distribution if an inspector believes they are adulterated or misbranded, but the agency lacked this authority for drugs. FDASIA has extended the agency’s administrative detention authority to include drugs as well, and the agency is taking steps to implement this authority. In addition, earlier this year the agency pushed for higher penalties for counterfeiting and intentionally adulterating drugs before the federal sentencing commission – and succeeded. 

 

These are the first of several provisions that we must implement under Title VII, the section of FDASIA that strengthens FDA’s authorities over the drug supply chain. The FDA hosted a public meeting on July 12, 2013 to discuss how the FDA might implement some of the other portions of Title VII specifically Section 7.13 Standards for Admission of Imported Drugs and Section 714 Registration of Commercial Importers and Good Importer Practices. 

FDA Commissioner Margaret Hamburg said during the meeting that administrative detention regulations for drugs will allow FDA to exercise the same authorities it has for food and medical devices, which are already subject to administrative detention and allow the agency to penalize manufacturers that interfere with FDA inspections.

“This is another significant tool for managing the supply chain because it will help ensure more immediate and consistent enforcement of the law,” Hamburg said of the guidance, adding that the provisions were the first two of several mandated actions the action would take on supply chain quality and security.

Rx-360 was asked to present at this public meeting and Martin VanTrieste, R.Ph, Rx-360 Board Member, spoke in support of the supply chain provisions within Title VII of FDASIA and how the FDA is implementing these requirements.  He said during his remarks “I believe that FDASIA will go a long way in leveling the playing field globally in the pharmaceutical industry,”   Rx-360's presentation and entire proceedings from the public meeting can be watched by clicking here.  

On July 15, 2013 the FDA published two items in the Federal Register that are required to implement sections of Title VII of FDASIA and strengthen the security of the pharmaceutical supply chain.  These represent two new powers given to FDA in FDASIA.  One is a proposed rule and the second is a draft guidance.  The comments on the proposed rule are due September 15, 2013 and comments on the guidance are due to FDA on September 13, 2013. Both items are summarized below:

Proposed Rule:  Administrative Detention of Drugs Intended for Human or Animal Use (FR Vol. 78, No. 135, pages 42382-42386, July 15, 2013)

The FDA currently has authority to administratively detain devices, tobacco and foods, but does not have this authority with regard to drugs.  FDA is proposing this rule to implement section 709 of FDASIA.  When finalized, this rule will give authority to FDA to “administratively detain drugs encountered during an inspection that an officer or employee conducting an inspection has reason to believe are adulterated or misbranded.”  Further, the proposed rule states that “…administrative detention is intended to protect the public by preventing distribution or subsequent use of drugs encountered during inspections that may be adulterated or misbranded, until FDA has had time to consider what action it should take concerning the drugs, and to initiate legal action, if appropriate.”  The proposed rule specifies:

  • The duration of administrative detention cannot exceed 30 days unless otherwise officially extended
  • The content of the detention order including the reason for detention, identification of the detained drugs, time/date of the detention order and details on appeals to this detention
  • How product subject to the detention order must be labeled/marked
  • How to appeal the detention order
  • How drugs under the order may be moved
  • Other actions that may be implemented and
  • How the order may be terminated

To view or download the proposed rule, click here

To view or download Rx-360 Summary of proposed rule, click here

 

Draft Guidance for Industry;  Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection (FR Vol. 78 No. 135, page 42387, July 15, 2013)

This draft guidance is published in support of section 704 and 707 of FDASIA which state that refusal of inspection is subject to criminal penalties and that a drug is deemed to be adulterated if an “…establishment delays, denies or limits an inspection , or refuses to permit entry or inspection”  respectively. The guidance identifies actions that FDA will consider in making a decision that an inspection has been delayed or denied.  The guidance provides examples of what constitutes the following actions:

  • Delay of Inspection for preannounced inspections, delay during an inspection and delay in producing records
  • Denial of Inspection
  • Limiting the inspection including limiting access to the facility and manufacturing process, limiting photography, limiting access to or copying of records, and limiting or preventing sample collection
  • Refusal to permit entry or inspection

To view or download the FDA Guidance, click here

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

 

To help the public keep track of FDA's progress on these and other provisions, the FDA established a FDASIA web portal that includes a link to our three year implementation plan, which we intend to update on a monthly basis. 

 

 

  

India's List of API Manufacturers Confirmed for Export to EU Minimize
 

India's List of API Manufacturers Confirmed for Export to EU

Rx-360 Issued: July 2, 2013

 

India’s Central Drugs Standard Control Organization (CDSCO) has posted a List of Written Confirmations Granted that sets forth  57 active pharmaceutical ingredient (API) manufacturing sites in India that have been confirmed by the CDSCO as complying with the good manufacturing practice (GMP) requirements mandated by the EU for API imports as of 2 July 2013.

India is a major exporter of API’s and the List may be seen as welcome in Europe, given that the Heads of Medicines Agencies (HMA) – the heads of member state national regulatory agencies – sent a letter to the European Commission expressing concern that the Falsified Medicines Directive, which mandates the new rules governing API imports, might lead to a shortage of drugs in Europe.

 

 

  

In Last-Minute Decision, EU Says US Clear to Export APIs Under Falsified Medicines Directive Minimize
 

At the Last-Minute, EU Says US Clear to Export APIs Under Falsified Medicines Directive

Rx-360 Issued: June 22, 2013

The Falsified Medicines Directive requires that APIs imported into the EU are accompanied by a written confirmation from the regulatory authorities in the exporting country stating they are manufactured under GMPs  essentially equivalent to the EU GMPs.  This requirement becomes effective July 2, 2013. 

Concerns have been raised by industry that this requirement may result in drug shortages in the EU.  On June 19, 2013 the European Commission confirmed that the US will be among the “listed” countries, effective June 26, 2013,  and APIs imported from the US will not require a written confirmation.  Four countries are now among the “listed” countries:  Switzerland, Australia, Japan and the United States.  Brazil’s application is under consideration.  The applications from Singapore and Israel have been declined pending changes in their GMPS to adequately address APIs that are exported rather than manufactured into drug product in domestically.  China, India,  and Canada, among others, have either begun providing the necessary written confirmations or will do so by July 2, 2013.

To read EC Announcement, click here

 

  

EMA has issued Q&As addressing GMP requirements for active substances Minimize
 

Rx-360 Issued: June 2, 2013

 

EMA has issued Q&As addressing GMP requirements for active substances

 

The EMA recently issued several new Q&As that address GMP requirements for active substances.  These are questions 8, 9, and 10 and can be read in their entirerity by chicking here.  The responses address review of audit reports by agency inspectors, expected content of audit reports, and qualification of the auditors who perform inspections of active substance manufacturers.  Briefly, responses to each of the questions are summarized below:
 
QUESTION 8:  Inspectors review audit reports as part of their assessment that the Manufacturing Authorization Holder provides adequate oversight and evaluation of the active substance manufacturer.  The documentation shown to inspectors should contain all details of the audit including responses and follow up to indicate closure of any deficiencies identified during the audit.

QUESTION 9:  A very detailed, nearly two page, response is given to the question regarding the expected content of an audit report issued after audit of an active substance manufacturers.  Briefly, some of the information should include:

  • The report should contain details on the address of the auditee, the duration of the audit, and the specific function of the site being audited. 
  • The audit report should identify the scope of the audit and the standards against which the audit is conducted.  The response identifies seven specific areas that should be evaluated in addition to other identified high risk areas or concerns. 
  • The report should identify whether the operations occur in multi-product facility or multi-product equipment.
  • A proposed reassessment interval should be included and the report should be signed by the lead auditor.

QUESTION 10:  Auditors should be appropriately trained for their anticipated role in audits of active substance manufacturers.  Those who do not have “…an appropriate level of direct experience in the field of active substance manufacture…” should receive documented training in appropriate topics.  In addition, auditors should have training and be assessed on their knowledge of the EU GMP Guide Part II.  Finally qualifications of contracted auditors should be the same as the auditors of the Manufacturing Authorization Holder.

 

  

Health Canada Regulations Amending the Food and Drug Regulations (1475 — Good Manufacturing Practices) Minimize
 

Rx:260 Issued: June 4, 2013

Health Canada Regulations Amending the Food and Drug Regulations (1475 — Good Manufacturing Practices)

On May 8, 2013 Health Canada published the final GMP regulations revised to include Active Pharmaceutical Ingredients (APIs).  This represents an effort to ensure adequate control over the whole of the pharmaceutical supply chain.  Health Canada undertook this effort to align with other “industrialized countries” with incorporation of API requirements into their GMPs.  The effective date for the GMP requirements for API is 6 months after its publication.  Further, companies will have until February 2014 to submit an establishment license application, and still be considered in compliance.  Many of the requirements seem to align with ICHQ7, GMPs for Drug Substance, though specific labeling requirements are being implemented to allow tracking of APIs from the actual manufacturer to the manufacturer of the dosage form. Health Canada indicates that incorporating API requirements will allow work-sharing of inspection responsibilities with those countries with which it has a Mutual Recognition Agreement (MRA).  

 

To View or Download the Heath Canada
Regulations,
click here

 

To View or Downlaod the Rx-360 Summary
of the Regulations,
click here

 

  

USP Elemental Impurities Update Minimize


Rx-360 Issued: May 28, 2013

The recent Rx-360 newsletter included an article that addressed the complications around the upcoming implementation of the USP General Notices section 5.60.30 , Elemental Impurities.  This general chapter was to be effective May 1, 2014.  US Pharmacopeia issued a Compendial Notice on May 24, 2013 indicating that the effective date of the new General Notices section 5.60.30 Elemental Impurities  has been deferred from the May 1, 2014 target.   As a result, there “is no requirement for any drug product in the USP-NF to comply” with the already published Chapters <232> Limits and <233> Procedures.  In addition, “the proposed omission of General Chapter <231> Heavy Metals also has been deferred.” 

This decision by the USP Executive Committee of the Council of Experts is a result of significant comments received by USP in response to the publication of the draft General Notice section 5.60.30  / <231> in the Pharmacopeial Forum volume 39 (1) (January 2013).   The USP notice refers to the main issue raised by industry groups:

“These deferrals will allow USP to work closely with ICH Q3D to align their activities with the implementation of General Chapters <232> and <233>. The deferral also allows USP to work with those affected by the new elemental impurity standards.  In this regard, USP plans to form an Advisory Group on the Implementation of General Chapters <232> and <233>.”

This cooperation between USP and ICH will result in a more harmonized standard, and allow industry to adapt to the change from the outdated Heavy Metals testing methodologies and limit requirements with the knowledge that the standard will be global.

 

 

  

Contract Manufacturing Arrangements for Drugs: Quality Agreements Minimize
 

Rx-360 Issued: 28-May-2013

On May 28, 2013, the FDA issued draft guidance: Contract Manufacturing Arrangements for Drugs:  Quality Agreements.”  Comments are due to FDA by July 29, 2013.  The following products are within the scope of the guidance: human and veterinary drugs, some combination products, drug products, APIs and intermediates and the drug constituents of combination drug/device products.  In the draft, FDA reinforces their existing position that the owner of the drug who introduces the drug into interstate commerce “ 

 “is responsible for assuring that drugs…are neither adulterated nor misbranded as a result of the actions of their selected Contracted Facilities.”  A Quality Agreement should contain at least the following sections:  Purpose/Scope, Terms, Dispute Resolution, Responsibilities, and Change control and revisions.  Within the section describing “Responsibilities”, the draft guidance provides specific detail with regard to:

  • Quality Unit responsibilities(this section is the longest and most detailed)
  • Facilities and equipment
  • Materials management
  • Product specific requirements and responsibilities
  • Laboratory Controls
  • Documentation

Section V of the guidance provides specific examples of problems that can arise in contracted manufacturing arrangements with respect to facilities and equipment, documentation of the manufacturing process, and contracted laboratory services.  FDA describes actions that may be taken against the owner and the contracted facility depending on the specifics of the issues in question.  In all examples, the owner of the product is ultimately responsible for quality of the commercial product even though it may contract out significant portions of manufacture and testing.  The contract facility is responsible to comply with CGMP requirements independent of what might be specified in the Quality Agreement.

To view or download the FDA Draft Guidance, click here

 

 

  

UN Report on Transnational Organized Crime in East Asia and the Pacific. Minimize
  

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 PacificThis 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




 

  

FreightWatch 2013 Global Cargo Theft Threat Assessment Minimize

 

 

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

 

 

  

EC Falsified Medicines Directive Minimize

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. 

 

 

  

Summary the US House of Representatives hearing entitled Securing Our Nation’s Prescription Drug Supply Chain Minimize

 

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:

 

 

  

Guideline on the use of porcine trypsin used in the manufacture of human biological medicinal products Minimize

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.

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

 

  

Importation of Active Substances For Medicinal Products for Human Use, Questions and Answers, Version 4.1 Minimize

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.


To view or download the Q&A, click here


 

  

Rx-360 Summary of New Saudi FDA Guidance for the Storage and Transport of Time and Temperature Sensitive Pharmaceutical Products Minimize
 

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

 

  

US FR Notice About FDA Enforcement of FDAISA Minimize

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.


To View or download the Federal Register Nocite, click here

 

  

Rx-360 Summary EC Importation of Active Substances for Medicinal Products for Human Use, Questions and Answers Minimize
EC 2

Rx-360 Issued: April 6, 2013

 

The European Commission recently published version 4 (April 4, 2013) of the Importation of Active Substances for Medicinal Products for Human Use, Questions and Answers.  This supersedes the version published in January 2013 and adds three new questions and answers. 


  • Question 2a addresses whether the written confirmations apply to blood plasma.  The EC responded “no”.  However they clarify that substancesisolated from blood plasma are considered active substances and in this case written confirmation is required.
  • Question 10a asks whether starting material that undergoes additional purification or chemical synthesis in the production of an active substance requires written confirmation if imported into the EU.  The EC responded “no”, starting materials such as those that undergo additional purification or chemical synthesis do not meet the definition of materials that require a written confirmation.

  • Question11b addresses the manufacture of finished dosage forms that are intended for export only.  The EC responded “yes”, the API that is incorporated into a finished dosage form, manufactured in the EU but intended for export only, would require written confirmation.

​To view or download the EC Q&A, click here

 

 

  

“Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement International Organization for Standardization (ISO) Standard 11040-4”. Minimize

  

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.

According to the draft guidance “The reported events occurred upon attempted connections between the needleless glass syringe and certain needles or needleless pin activated luer connectors.  The events included syringe tips breaking upon injection, needles detaching during injection and syringes breaking or jamming the IV lines or other patient use lines.”   Prior to these events, FDA considered that compliance with the relevant ISO standard, ISO-11040-4 would be adequate.  

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


 

  

EMA Draft Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities Minimize

EMA Draft Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities

 

Rx-360 Issued: March 30, 2013 

The European Medicines Agency (EMA) has issued a draft Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/ CHMP/ CVMP/ SWP/ 169430/ 2012).

 

The current standard cleaning validation approach targets a reduction of the concentration of residual active substance to a level where the maximum carryover from the total equipment train would result in no greater than 1/1000th of the lowest clinical dose of the contaminating substance in the maximum daily dosage of the next product to be manufactured.  This criterion was applied concurrently with a maximum permitted contamination of 10 ppm of the previous active substance in the next product manufactured.  Whichever of these criteria resulted in the lowest carryover, constituted the limit applied for cleaning validation.  In this draft Guideline, the EMA is proposing to adopt a more scientific and data-focused approach, and specifically proposes to revise Chapters 3 and 5 of the GMP guideline to refer to a “toxicological evaluation” for establishing threshold values for risk identification.  (The revisions are incorporated into the recently released Chapters 3 and 5 as previously reported by Rx-360).  The Guideline applies to all human and veterinary medicinal products, including investigational medicinal products, and all active substances that are intended for manufacture in premises used for the manufacture of other products or active substances.

 

The draft Guideline proposes a procedure to determine health based exposure limits based on the “Permitted Daily Exposure” (PDE) as described in Appendix 3 of ICH Q3C (R4) “Impurities: Guideline for Residual Solvents” and Appendix 3 of VICH GL 18 on “residual solvents in new veterinary medicinal products, active substances and excipients (Revision)”.  The draft outlines specific considerations for development of the PDE values, as well as the elements of a Risk Assessment Report.

 

The draft Guideline is open for consultation and the deadline for comments is 30 June 2013.

To view or download the draft guidance, click here

 

 

 

 

  

China SFDA Published a Good Supply Practice Guidance Minimize

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

 

  

EMA Has Release Draft Revisions of Four GMP Guideline Chapters Minimize
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

 

  

EU GDPs Minimize

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

 

 

 

  

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

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 Minimize
 

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 Draft Guidance Documents for Public Consultation Minimize

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:


Guidelines on the Principles of Good Distribution Practice for Active Substances for Medicinal Products for Human Use. This document describes requirements for distribution practices for APIs with requirements to ensure transparency, knowledge and control of the supply chain.  While this Guideline specifically addresses APIs, the soon-to-be published Guideline on GDP which will become part of Part III of the EU GMP Guideline more completely addresses drug product. 

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 Minimize

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

 

  

Indian Good Distribution Practices Minimize

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.  

  The purpose of the draft is to ensure consistent quality of pharmaceutical products throughout the distribution process where all parties in the supply chain contribute to maintaining the quality of products until they reach the patient.  This includes, but is not limited to the activities of  “procurement, purchasing, storage, distribution, transportation, documentation and record-keeping.”  The guideline refers to the previously finalized Good Distribution Practices for Biological Products for specific issues associated with biological products, although biological products are within the scope of this document for general requirements.  

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

 

  

ANVISA Seeks Consultation on GMPs and GDPs Minimize

  

ANVISA
 

ANVISA Requests Feedback On The Conditions For Granting The Certification of GMP And GDP

ANVISA released a proposal for consultation on January 7, 2013 describing the conditions for granting the Certification of Good Manufacturing Practice (GMP) and Certification of Good Distribution and/or Storage Practice (GDSP).  Consultation on this proposal will be accepted for 60 days.  When the final document is published, it will become effective 7 days later.  The document covers a wide range of product types, including drug products and intermediates, cosmetics, perfumes, personal hygiene products, and cleaning products.  The requirements are specified  by product type.  The requirements for drug products and intermediates include a variety of product types:  sterile products, non-sterile solids, non-sterile liquids, non-sterile semi-solids, gasses and biologicals.  Specific detail may be found within the slide deck.

To view or download the ANVISA Proposal for Consultation, click here

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

  

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 Minimize

 

 

 

               

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

 

  

US FDA Set to Release Final Rule on GMPs for Combination products Minimize

U.S. FDA Set to Publish Final Rule for Combination Product GMPs

Rx-360 Issued: 22-January-2013

 

ComboOverview2  The GMPs for Combination Products will be published in the Federal Register soon.  The draft rule published for comment in September 2009 and the final rule is very similar to the draft rule; the background and preamble to the final rule should be read because they include FDA’s specific comments and interpretation of requirements.  Guidance will be necessary to promote consistent implementation of the rule and the rule mentions this will be forthcoming. 
 
Each component, drug and device, will need to comply with the existing regulations specific to the component. When combined in a combination product, “…each of the constituent parts remains subject to its respective cGMP requirements.”
    
For certain classes of combination products, companies have the choice of complying with either all of the GMP requirements for both components or taking a streamlined approach whereby the company documents compliance with either the drug GMPs or the QS regulations along with demonstrating of compliance with specified provisions of the other of the two components.

For example, if a company claimed compliance with the 21 CFR 210 and 211 (including parts 600-680 if appropriate), these would need to be supplemented by compliance with the following Quality System regulations for a combination product:
  • §820.20, Management Responsibility
  • §820.30, Design Controls
  • §820.50, Purchasing Controls
  • §820.100, Corrective and Preventive Action
  • §820.170, Installation
  • §820.200, Servicing

This rule will become effective 180 days after publication, which may prove a challenge to those firms that are incorporating segments of the 820 regulations for the first time.  The agency states that 180 days should not be a problem for implementation because they are only streamlining existing rules. 

To view or download the Final Rule, click here

  

India published “Guidelines on Recall and Rapid Alert System for Drugs (Including Biologicals & Vaccines)" Minimize

India published “Guidelines on Recall and Rapid Alert System for Drugs (Including Biologicals & Vaccines)” 

Rx-360 Issued: 21-January-2013

 Rx-360 Issued: 21-January-2013

 

 

Central Drugs Standard Control Organisation (CDSCO) of India published “Guidelines on Recall and Rapid Alert System for Drugs (Including Biologicals & Vaccines)” with an effective date of November 23, 2012.  Prior to this guideline there was no consistent “effective and uniform recall procedure, with time lines...”.  The guideline applies to both human and veterinary drugs. 
The Guideline identifies three classes of recalls based on the relative risk to public health, and identifies options for both voluntary recalls initiated by the company and statutory recalls initiated by the regulatory authority.  The Rapid Alert Notification is to be used in those instances where the potential seriousness of the impact on public heath requires very quick action in notification and recall of product.  Pages 1-13 describe the requirements for the rapid alert notification and recalls, and the following 13 pages include CDSCO SOPs and forms on this topic.  

   To view or download the Indian recall process, click here

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

  

ANVISA Published Requirements for Excipient GMPs Minimize
Brazil’s ANVISA Published Requirement for GMP Compliance by Manufacturers of Pharmaceutical Excipients

Rx-360 Issued: January 14, 2013
 
On May 28, 2012, Brazil’s ANVISA published a draft Resolution that would require GMP compliance by manufacturers of pharmaceutical excipients.  The consultation period of 60 days began seven days after its publication. Rx-360 recevied the following question  

Question: When these requirements were first published, Rx-360 received a variety of input as to whether this just applied to drug product manufactured in Brazil or did it apply to drug product IMPORTED into Brazil or some combination thereof?  

Answer: The ANVISA response to the Swiss authority, question and response attached here, clearly states that “at this time it applies only to Brazilian companies”.


Requirements for Drug Product Made in Brazil: The GMPs for excipients in this draft act include eight chapters generally reflective of the type of requirements that are applied to human medicinal products and their APIs.  If this Resolution is finalized as written it would require manufacturers of excipients to comply with the following general requirements:

  • General Considerations
    • Excipient manufacturers must hold a working authorization and sanitary license
    • Excipient manufacturers would be subject to inspection by the competent authorities
    • The manufacturer must state and justify at which point GMPs are applied based on the step(s) in the process where the quality of raw materials and intermediates can have “critical influence” on the quality of the excipient
  • Quality Management including specified responsibilities of the Quality unit and requirements for self inspection
  • Personnel: including general hygiene, health exams, GMP training, and prohibitions on the wearing of watches, jewelry and makeup in areas where product is exposed
  • Buildings and Facilities
  • Prohibition of the manufacture of highly toxic non-pharmaceutical ingredients in the same facilities or equipment as excipients
    • Cleaning and sanitization of equipment, cleaning of facilities and pest control expectations
    • Disposal of waste materials
  • Equipment
  • Documentation and Records
  • Materials Control including sampling, testing, reuse and rework, solvent recovery, and prohibition against blending to meet quality standards
  • Production including expectations regarding water quality
  • Packaging, Labeling and Dispatch including specific information that must be on the label
  • Quality Control for raw materials, in process streams, final excipient, retention samples, control of impurities and stability evaluation to support retest or expiry dating
  • Change Control
  • Complaints Recalls and Returns
  • The draft states that while the Resolution will take effect on the date of its publication, existing establishments will have 12 months to fully comply.  New facilities must fully comply immediately and are not provided with the 12 month grace period.
To view or download the ANVISA Draft Resolution, click here

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

To view or download the question on applicability by the 
Swiss Authority,
 click here

To view or download the ANVISA response to the 
Swiss Authority,
 click here

 

  

 

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