Friday, April 18, 2014
2014 Summaries Minimize

European Commission (EC) published the revised Chapter 6: “Quality Control” of the Volume 4 Minimize

European Commission (EC) published the revised Chapter 6: “Quality Control” of the Volume 4

Rx-360 Issued: 11-April-2014

On the 28th March 2014, the European Commission (EC) published the revised Chapter 6: “Quality Control” of the Volume 4 of the guidelines for Good Manufacturing Practices (GMP) for Medicinal Products for Human and Veterinary Use. The document will be effective on the 1st October 2014.

The revised Chapter 6 on quality control contains a new section on analytical method transfer (section 6.37: “Technical transfer of testing methods”) that points to the need for verifying that the test method(s) comply with those as described in the Marketing Authorisation (MA), establishing a method transfer protocol and provide recommendations on what the protocol should contain.

Also added is an emphasis on the importance of investigating out of specification (OOS) trends in laboratory data. The final document notes that a procedure for the investigation of OOS, out of trend (OOT) results and “anomalous results” should be in place and that the results should be addressed and recorded in a manner that permits trend evaluation.

The revision introduces the notion of a risk based approach regarding the sampling plans.

In section 6.23 and 6.24, the revised Chapter 6 set forth requirements for culture media and strains management.

Moreover, the document highlights that the samples should be managed in order to minimize risk of mix-up and to protect from adverse storage conditions.

Finally, Chapter 6 states that documentation retention should be performed according to Chapter 4 “Documentation” of the Volume 4.


To view or download the EC Revised Chapter 6, click here



EU – Good Distribution Practice for Medicinal Products for Human Use – Questions and Answers Minimize

EU – Good Distribution Practice for Medicinal Products for Human Use – Questions and Answers

Rx-360 Issued: 10-April-2-14

On 28 March 2014 the European Commission published a question and answers document related to the new guideline on Good Distribution Practice of medicinal products for human use applicable as of November 2013.

The Q&A document contains 25 questions and answers. The questions focused mainly around:

  • Competence and training of personnel (chapter 2)
  • Segregation of products, temperature and environmental control, alarms and deviations (chapter 3)
  • Qualification of customer, verification of authorization for sale (chapter 5)
  • Control of returned products and recall procedure (chapter 6)
  • Transport requirements (temperature, safety) (chapter 9)

Some of the questions are simply for clarification and confirmation. Other questions may have become the basis for some discussion:

  • Question 5 (chapter 3.2(3)): It was confirmed that falsified, expired, recalled and rejected products need a physical segregation in any case. A validated computerized system (electronic segregation) cannot substitute in these cases.
  • Questions 7 & 8 refer to chapter 3.2.1. about temperature and environment control. The EU commission highlights the importance of risk assessments as basis for the design of temperature mapping studies and the positioning of monitoring sensors. Further clarification on the design of mapping studies was given (e.g. studies to be performed in different seasons).
  • Questions 13 & 14 are related to product authorization for sale (chapter 5.4.(3)). Different requirements are applicable dependent on the origin of the product (EU member state or not). But in any case the wholesalers need to verify that a batch of medicinal products is authorized for sale in the target state (provision applicable today independent of potential future implementation of safety features allowing traceability through a database).

Question 22 (chapter 9.2.(1)): Some stakeholders proposed to allow transport conditions which may deviate from the standard storage conditions, e.g. greater temperature range for a limited time frame. The EU Commission clearly states that this procedure would not be acceptable.

To view or download the EU GDP Document, click here



Guidance for Industry, Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products Minimize

Rx-360 Issued: 25-March-2014

FDA recently published a draft Guidance for Industry, Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products.  Comments are due to FDA by June 12, 2014.  This guidance applies to parenteral drug product provided in vials and is not applicable to drug product provided in pre-filled syringes and intravenous infusion bags.  Both original NDAs, BLAs, ANDAs and their supplements are included within the scope of this draft guidance.  FDA is concerned about “inappropriate excess volume and labeled vial fill sizes” may contribute to microbial contamination of drug product and possible medication errors.   

In this guidance, FDA notes that existing regulations require that sponsors/applicants comply with the “excess volume” recommendations in the USP <1151> for drugs in ampules and vials, intended for injection.  If the applicant chooses to deviate from the USP requirements, they must provide justification.

To view or download the FDA Guidance, click here

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



DRUG SHORTAGES, Public Health Threat Continues, Despite Efforts to Help Ensure Product Availability Minimize

DRUG SHORTAGES, Public Health Threat Continues, Despite Efforts to Help Ensure Product Availability

Rx-360 Issued: 12-March-2104

In 2012, FDASIA provided FDA with additional authority to address drugs shortage and also required GAO to study the drug shortage situation.  The GAO recently published a report: DRUG SHORTAGES, Public Health Threat Continues, Despite Efforts to Help Ensure Product Availability.  In this report GAO evaluates the high level causes of drug shortages and their impact on public health, evaluates the effectiveness of actions that FDA has taken to prevent and mitigate the impact of drug shortages, and makes recommendations for FDA to enhance its oversight of drug shortages.  

The GAO report also reviews economic causes of drug shortages, particularly for generic sterile parenteral products.  GAO acknowledges the progress that FDA has made in preventing shortages and mitigating their impact and suggests that FDA use their data to “…proactively identify drug shortage risk factors.”

 To view or download the GAO Report, click here

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


FDA Annual Report on the Inspection of Registered Establishments Minimize

FDA Annual Report on the Inspection of Registered Establishments

Rx-360 Issued: 06-March-2014

Section 705 of FDASIA, passed in July 2012, requires that FDA report annually on the inspection of registered establishments and post the information on their web site.  The reports are due no later than February 1 for the prior fiscal year.  This is the first of the reports and addresses the inspection activities of CDER, CBER, CVM and CDRH registered establishments in FY 2013.  The report does not cover establishments that manufacture only excipients because FDA databases do not current include these data.  Data in the report include:

  • Number of registered establishments
  • Number of foreign and domestic establishment inspections and
  • Percentage of the budget used to fund these inspections

To view or download the FDA Report, click here

To view or download the Rx-360 Summary of the FDA Reportclick here



First Annual Report on Drug Shortages Minimize

First Annual Report on Drug Shortages

Rx-360 Issued: 26-February-2014

On February 5, 2014, the FDA provided their First Annual Report on Drug Shortages to Congress as required by Section 1002 of FDASIA.  FDA believes that the increased notifications resulting from action by the Administration, Congress and FDA has allowed them to respond more effectively to shortages and potential shortages.  Pages 1-5 summarize the legal authority in this area and the guidances and actions FDA has taken so far to prevent and mitigate drug shortages.  

  FDA provides data on actions in this area, including but not limited to:
  • 39 different manufacturers notified FDA of 202 potential drug shortages.
  • The Office of Generic Drugs (OGD) expedited review of 118 applications including 62 ANDAs and 56 supplements; the office of biological products expedited review of 7 supplements; in total CDER expedited review of 177 applications that includes ANDAs/NDAs and supplements in the first three quarters of calendar year 2013.
  • 56 inspections were prioritized based on the applications / supplements that were granted expedited review.
  • Figure 1 shows the number of new drug shortages annually between 2005 and Q1-3 of 2013.  These increased to a high of 251 in 2011, decreased to 117 in 2012 and 38 for the first three quarters of 2013.  They conclude that “…in the first three quarters of 2013, we have prevented 140 shortages.”

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

To view or download the FDA report, click here




Draft EU GMP Annex 15 for Qualification and Validation Minimize

Draft EU GMP Annex 15 for Qualification and Validation

Rx-360 Issued: February 24, 2014

The EU has published for consultation Annex 15: Qualification and Validation (Volume 4 of Guidelines for GMP for Medicinal Products for Human and Veterinary Use). The draft comment period ends end of May 2014.  The revision takes into account changes to Part 1 of the EU GMP Guide, Annex 11, ICH documents Q8-11, the EMA Process Validation draft guidance, and changes in manufacturing technologies.  

The draft now includes principles drawn from ICH Q8, Q9, Q10 and Q11, including knowledge management (ICH Q8 & Q10), science and risk-based approaches (ICH Q9) to support lifecycle validation & qualification activities, and the use of a design space (ICH Q8) for Process Validation.

Other key points are:

  • Retrospective validation and the notion of revalidation are gone completely
  • User Requirement Specifications (URS) have been added to the section on Qualification for Facilities and Equipment, along with Factory Acceptance Testing (FAT) and Site Acceptance Testing (SAT)
  • Process Validation is divided into ‘Traditional’ and ‘Continuous Process Verification’ with a hybrid of the two allowed, as per the 2012 draft CHMP NfG on Process Validation
  • For the traditional validation approach, the number of batches manufactured and the number of samples taken should be based on quality risk management principles. This indicates a move away from the previous rule which required three validation batches
  • The term “ongoing process verification” is equated to “continued process verification”
  • "Bracketing" approaches for Process Validation can be used if justified
  • There is a new section on Verification of Transportation. Since validation of transport may be challenging due to the variable factors involved, continuous monitoring of critical environmental conditions should be performed. A risk assessment should be performed which also considers the impact of conditions other than temperature (e.g. humidity, vibration, handling)
  • A “visual check for cleanliness” may no longer be the only criterion for a cleaning validation
  • Cleaning validation is required to be based on a toxicological evaluation to determine the product specific permitted daily exposure (PDE) value, as per the drafts of Chapters 3 & 5 and the CHMP Guideline on setting health based exposure limits
  • The Annex no longer looks for three consecutive batches to demonstrate that the cleaning process is validated. It now states that cleaning process be carried out an “appropriate number of times based on a risk assessment”
  • New concept of cleaning verification for infrequently manufactured or for investigational products 
  • New sections added on:
    1. Ongoing Process Verification during Lifecycle
    2. Verification of Transportation
    3. Validation of Packaging
    4. Qualification of Utilities
    5. Validation of Test Methods


To View or Download the Draft of Annex 15, Click Here



Assessing the Risks of Counterfeiting and Illicit Diversion for Health Care Products Minimize

Rx-360 Summary of Michigan State University Center for Anti-Counterfeiting and Product Protection Risk of Counterfeiting Report

Rx-360 Issued: 09-February-2103

Michigan State University Center for Anti-Counterfeiting and Product Protection published a report titled “Assessing the Risks of Counterfeiting and Illicit Diversion for Health Care Products” in November 2013.  This report addresses the multiple risks of counterfeit and diverted health care products including adulteration with dangerous chemicals, and diluted / sub-potent APIs and dosage form.  The adulterations can happen either through inadvertent GMP failures or through intentional economic motivated adulteration.  Further complicating this issue is the fact that legitimate product that is not maintained under appropriate environmental conditions or handled incorrectly, as may happen with diverted health care products, may lose potency and become ineffective or even harmful.  

The paper identifies potential questions that should be considered in determining the potential risk to patients from a counterfeit or diversion incident (see pages 3-8).  Answers to these questions identify areas of concern that should be considered to mitigate the identified risks.  Such activities are meant to be ongoing and reviewed frequently as the landscape for these type of illegal activities changes rapidly.

To view or download the summary, click here

To view or download the report, click here



Flash Report re EU Q&A on Importation of APIs Minimize

EU Q&A on Importation of APIs


The Falsified Medicines Directive came into force in Europe in January 2013. Among the Directive’s requirements is the stipulation that APIs imported into the European Union meet equivalent GMPs to those applied in the EU.  To implement this requirement, manufacturers must obtain certification from the competent authority in the country where the API is manufactured that they were made in compliance with GMPs equivalent to those of the EU.  Alternatively, countries of origin may apply for exemption from this rule for APIs manufactured within their borders.  


To assist manufacturers, the European Commission published version 5.0 Questions and Answers regarding Importation of Active Substances for Medicinal Products for Human Use on November 13, 2013 which adds two new questions and answers - 33 and 34: 


Answer: A statement of GMP non-compliance issued by a EU Member State for a specific site and API supersedes the corresponding written confirmation until the noncompliance is resolved.


Answer: Statements of GMP non-compliance are stored in the EudraGMDP database ( They are currently accessible only by EU national competent authorities, but are expected to become publicly available by end of 2013.  Until then, a list of active manufacturing sites that received a statement of GMP noncompliance can be found here:

The EudraGMDP database referenced above now includes summary reports and reasons for non-compliance status identified during inspections.  It may be found at:



UPS Supply Chain Survey Minimize

Rx-360 Summary of UPS Supply Chain Survey

UPS has issued its sixth annual “Pain in The (Supply) Chain Survey.”  The survey results report that a majority of North America logistic executives view increasing regulations (54%) and changes in healthcare legislation (53%) as the top pain points for them.  These were also leading pain points in Western Europe.  In Asia, increased regulations and increasing competition were identified by over 50% of the survey responders.  Globally, half of the responders indicated they are still feeling the impact of the economic downturn.  Common themes in the survey include:

  • Logistics professional around the world identified accumulating supply chain and regulatory expertise as a best practice to address supply chain concerns. 
  • Utilizing new technology is also a common theme.  This includes order management, web ordering systems and temperature sensitive technologies. 
  • Companies are expecting to significantly increase investment in web ordering systems, e-pedigree and serialization technologies and security specific technologies over the next 5 years.

Click here to view of the UPS survey results

Click here to view the Rx-360 Summary




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