Regulatory Approval Pathways: EU vs US

Regulatory Approval Pathways: EU vs US

Drug Authorization Procedures in the EU 

Sponsors have several options when seeking market approval for a new drug in Europe: a national authorization procedure, a decentralized procedure, a mutual recognition procedure and a centralized procedure. Depending on a product’s eligibility, each of these authorization routes offers different advantages and disadvantages to the sponsor, and these should be considered when setting up the market strategy of a product.

National Procedure

This procedure is used whenever a company wants to commercialize a product in only one EU Member State.

The National procedure is specific to each country. That is, each country within the EU has its own procedures for authorizing a marketing application for a new drug. Sponsors can find information regarding the requirements and procedure of each country on the websites of the regulatory agencies.

ADVANTAGES of National Procedure

There are some advantages in submitting a MAA through this procedure. First, it allows the sponsor to choose which country the company will submit to first. This is especially advantageous when the sponsor can’t afford to go through the centralized or decentralized procedure, due to lack of resources of distribution infrastructure for example. Choosing the country that the sponsor is most familiar with in regards to its regulation can also be an important factor.  The national authorization procedure also allows the sponsor to, further down the line, get his drug approved through the mutual recognition procedure, seeing as one country already approved its drug. Overall, this procedure is less resource heavy than the others, and thus it is the cheapest and safest alternative for a sponsor.

DISADVANTAGES of National Procedure

The disadvantages are obvious, seeing as this procedure only allows the sponsor to commercialize in one single market, cutting potential revenue streams it could have by bringing the drug to more markets.

Centralized procedure

The centralized procedure is a Europe wide authorization procedure, conducted by EMA’s Committee for Human Medicinal Products (CHMP), an organization which has representatives of all Member states, EEA members, patient organizations and health professionals.

When a sponsor applies for drug approval through the Centralized Procedure, two member states are first selected, a rapporteur and a co-rapporteur. These two member states will be responsible for the creation of an evaluation report that will be assessed by the CHMP.  First, a draft report is prepared and sent to the committee for review. The committee prepares a set of questions to send to the sponsor. After receiving a response, further discussions continue and a final evaluation report is arranged, containing a positive or negative opinion. This whole process can take up to 210 days. After the report is completed, it is sent to the European Commission in less than 15 days. The European Commission has the final say on the matter, granting the MA or not after evaluation of the CHMP’s report. The EC’s decision is applicable to all Member States of the European Union and EEA states – Iceland, Norway e Liechtenstein. After approval from the EC, the MA is valid for five years.

The centralized procedure, when it was introduced by Regulation (EEC) no 2309/93, followed the footsteps first established by Directive 87/22/EEC with its concertation procedure , and it was first made obligatory to products made from Recombinant DNA technology, controlled gene expression and monoclonal antibodies.

Afterwards, Regulation (EC) No 726/2004 extended the scope of the procedure to include orphan medicinal products and new active substances for the treatment of acquired immune deficiency syndrome (HIV), cancer, neurodegenerative disorder or diabetes. It went into force in 20th November 2005.

Recital 8 and Point 3 of the Annex to Regulation (EC) No 726/2004 also established that, starting 20 May 2008, the centralized procedure would be obligatory for drug products containing new active substances for the treatment of autoimmune diseases and other immune dysfunctions and viral diseases.

Lastly, regulation EC No 1394/2007 made the procedure compulsory for Advanced Therapy Medicinal products, like gene therapy, tissue engineered and somatic cell therapy products.

Article 3(2) of Regulation (EC) No 726/2004 defines the optional scope of the centralized procedure. It states that the procedure can be followed optionally by medicines that contain a new active substance, or if the applicant shows that the therapeutic entity provides a significant therapeutic, scientific or technical innovation, and it would be in the best interest of public health if it was approved at a community level.

ADVANTAGES of Centralized Procedure

Products authorized through the centralized procedure are granted marketing authorizations that cover all EU member states and the EEA, a big, 500 million user market where the sponsor can potentially recoup the losses from drug development. The drug will be commercialized in all countries with a single, unique brand name.

The convenience of the centralized procedure is however accompanied by fees that are significantly higher than the national procedure’s.

DISADVANTAGES of Centralized Procedure

Also, it is also a very risky, all or nothing procedure. If the CHMP refuses an application, the drug is barred from sale in every EU country, whereas if the sponsor tried another authorization procedure, there was the possibility of getting approval in at least one country. Since the sponsor can’t choose the rapporteur countries like he can in other procedures, this also leaves him at a disadvantage.

Mutual Recognition Procedure

This procedure requires the drug to be already approved in a MS.

This procedure is based upon the principle that a marketing authorization and the evaluation in one Member State (the so-called reference Member State) ought to be recognized by the competent authorities of the other Member States (the so-called concerned Member States), that is, if a Member State concedes a national MA to a drug, other Member States can recognize the evaluation conducted by it and grant a MA for the drug themselves.

It’s also noteworthy to point out that both a Member State and the Sponsor can trigger the Mutual Recognition Procedure.

After the first marketing authorization in the Community is granted, the marketing authorization holder may request one or more Member State(s) to recognize an authorization approved by the reference Member State, by submitting an application in accordance with Article 28 of Directive 2001/83/EC.

Within 90 days of receipt of a valid application, the reference Member State will provide the assessment report together with the approved summary of product characteristics, labeling and package leaflet to the concerned Member States and to the marketing authorization holder.

Within 90 days of the receipt of these documents, the concerned Member States shall recognize the decision of the reference Member State and the approved summary of product characteristics, package leaflet and labeling by granting a MA.

If any country refuses to grant a MA by safety reasons, the matter will be taken to The Co-ordination Group for Mutual Recognition and Decentralized Procedures, which will attempt to make all member states reach a consensus in 60 days. If it fails, the request will be taken to the CHMP and treated like a centralized procedure.

Decentralized procedure

The decentralized procedure works in a similar way as the mutual recognition one, except here the medicinal product in question has not yet received a marketing authorization in any Member State at the time of application. Like the MRP, a reference member state is chosen, which will evaluate the MAA. The remaining member states then proceed to give their opinion on the evaluation. If all concerned member states agree on the evaluation by the reference member state, the drug will be approved and allowed for sale in those countries. If a member state disagrees, the Co-ordination Group for Mutual Recognition and Decentralized Procedures will, like in the MRP, play a referee role.

ADVANTAGES and DISADVANTAGES of MRP & Decentralized Procedure

Both the MRP and the decentralized procedure carry a set of advantages and disadvantages that sponsors ought to know before setting their product market strategy. Both of them allow a sponsor to avoid the need to go through different national procedures in each country. Moreover, they aren’t as risky as the centralized procedure, and, in the case of the MRP, the sponsor can choose the reference member state that will conduct the evaluation of the drug product (by first attaining a MA in that country). In both these procedures, fees have to be paid to all Member states who participate in the process, and, unlike the centralized procedure, the sponsor may have to attribute a different name for its drug product in different Member States., which may hurt brand awareness.

The MRP often sees disagreements between member states, holding up the procedure and causing delays. In these occasions, a lengthy dispute solving mechanism has to be employed, costing both time and money to the sponsor

The decentralized procedure avoids some of the potential disputes between member states by engaging each of the member states the applicant wishes to apply to at the time the first marketing authorization is made. Disputes are this less common in the decentralized procedure than in the MRP. Lastly, the decentralized procedure is faster than the MRP.  The first can take up to 210 days to complete its two steps. The MRP, on the other hand, a national MA is first needed, which can take up to 210 days, alongside the update period of the MA license before the MRP procedure starts proper, which can take more 180 days. The take home message is that there is no one-size fits all in regards to drug authorization procedures. Each one of the four available has different advantages and disadvantages, which have to be carefully weighed out by the sponsor.

Drug Approval Process for the US

Types of Applications Submitted to the US FDA for New Medicines/Treatments

Investigational New Drug (IND) – Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines.

New Drug Application (NDA) – When the sponsor of a new drug believes that enough evidence on the drug’s safety and effectiveness has been obtained to meet FDA’s   requirements for marketing approval, the sponsor submits a new drug application (NDA) to FDA. The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.

Biologic License Application (BLA) – Biological products are approved for marketing     under   the provisions of the Public Health Service Act. The Act requires a firm who manufactures a    biologic for sale in interstate commerce to hold a license for the product. A biologics license   application is a submission that contains specific information on the manufacturing processes,  chemistry, pharmacology, clinical pharmacology and the medical effects of the biologic product. If the information provided meets FDA requirements, the application is approved and a license is issued allowing the firm to market the product.

US Drug Approval Process

If an IND drug survives the clinical trials (phase 1-3), an NDA is submitted to the FDA. An NDA contains all the preclinical and clinical information obtained during the testing phase. The application contains information on the chemical makeup and manufacturing process, pharmacology and toxicity of the compound, human pharmacokinetics, results of the clinical trials, and proposed labeling. An NDA can include experience with the medication from outside the United States as well as external studies related to the drug.

After receiving an NDA, the FDA completes an independent review and makes its recommendations. The Prescription Drug User Fee Act of 1992 (PDUFA) was designed to help shorten the review time. This act allowed the agency to collect user fees from pharmaceutical companies as financial support to enhance the review process. The 1992 Prescription Drug User Fee Act (PDUFA) established a two-tiered system – Standard Review and Priority Review.

Standard Review is applied to a drug that offers at most, only minor improvement over existing marketed therapies. The 2002 amendments to PDUFA set a 10 month goal for a standard review.

Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where none existed. The goal for completing a Priority Review is six months.

If during the review the FDA staff feels there is a need for additional information or corrections, they will make a written request to the applicant. During the review process it is not unusual for the FDA to interact with the applicant staff.

The following four FDA programs are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening3 condition: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation.

Drug development in the fast lane: FDA approaches to expedited approval.

Fast track designation applies to the drug (either alone or in combination with other drugs) and the specific use for which it is being studied. The term drugrefers to the combination of two or more drugs if the combination is the subject of the fast track designation or request. Where appropriate, FDA may grant designation to the development of a new use of an approved drug.

  1. Serious Condition
  2. Demonstrating the Potential to Address Unmet Medical Need

The type of information needed to demonstrate the potential of a drug to address an unmet medical need will depend on the stage of drug development at which fast track designation is requested. Early in development, evidence of activity in a nonclinical model, a mechanistic rationale, or pharmacologic data could be used to demonstrate such potential. Later in development, available clinical data should demonstrate the potential to address an unmet medical need.

BREAKTHROUGH Therapy Designation

Section 506(a) of the FD&C Act provides for designation of a drug as a breakthrough therapy “. . . if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” It is important to recognize that the standard for breakthrough therapy designation is not the same as the standard for drug approval. The clinical evidence needed to support breakthrough designation is preliminary. In contrast, as is the case for all drugs, FDA will review the full data submitted to support approval of drugs designated as breakthrough therapies to determine whether the drugs are safe and effective for their intended use before they are approved for marketing.


The accelerated approval provisions of FDASIA in section 506(c) of the FD&C Act provide that FDA may grant accelerated approval to:

. . . a product for a serious or life-threatening disease or condition . . . upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

For drugs granted accelerated approval, post marketing confirmatory trials have been required to verify and describe the anticipated effect on IMM or other clinical benefit

Post marketing surveillance is important, because even the most well-designed phase 3 studies might not uncover every problem that could become apparent once a product is widely used. Furthermore, the new product might be more widely used by groups that might not have been well studied in the clinical trials, such as elderly patients. A crucial element in this process is that physicians report any untoward complications. The FDA has set up a medical reporting program called Medwatch to track serious adverse events (1-800-FDA-1088). The manufacturer must report adverse drug reactions at quarterly intervals for the first 3 years after approval, including a special report for any serious and unexpected adverse reactions

Regulatory Links for the US FDA Guidances

Guidance for Industry -Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014

Good Review Practice: Refuse to File, available on the Internet at and CBER SOPP 8404, Refusal to File Procedures for Biologic License Applications (August 27, 2007), available on the Internet at

Regulatory Links for the EU:

Directive 2001/20/EC of the European Parliament and of the Council of 4 April2001 on the approximation of the laws, regulations and administrative provisions of the MS relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

Detailed guidance on the request to the competent authorities for authorization of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01)

EFPIA: Status of the implementation of the European Union Clinical Trials

Directive at member state level, Circular N° 12.784 , June 2008

Klingmann I et al. Impact on Clinical Research of European Legislation. Final report, February 2009

Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC, Public Consultation Paper, ENTR/F/2/SF D(2009) 32674 10_09_public-consultation-paper.pdf

Report of the multidisciplinary workshop on “A single CTA in multinational clinical trials – dream or option?”, Brussels, Belgium, 7 July 2009

Clinical Trials Facilitation Groups, Guidance document for a VoluntaryHarmonization Procedure (VHP) for the assessment of multinational Clinical Trial Applications, Version 2 ; Doc.ref.: CTFG/VHP/2010/Rev1, March 2010

European Commission Enterprise Directorate-General. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use (ENTR/CT2), Revision 1, February 2006 60216.pdf

The EFGCP Report on The Procedure for the Ethical Review of Protocols forClinical Research Projects in Europe, Update April 2010

European Commission-European Medicines Agency Conference on the Operation of the Clinical Trials Directive (Directive 2001/20/EC) and Perspectives for the Future, Report on the Conference held on 3 October 2007 at the EMEA, London, Doc. ref.: EMEA/565466/2007

Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC,Summary of responses to the public consultation paper, SANCO/C/8/SF/dn D(2010) 380240

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to Medicinal Products for Human Use, as amended _83_de.pdf

Responses to the Public consultation paper “Assessment of the functioning of the ‘Clinical Trials Directive’ 2001/20/EC”, March 2010 developments/responses_2010-02_en.htm

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004

Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such products

European Commission, Impact Assessment, 2010 Roadmaps “Legislative proposal on a Regulation/Directive amending the Clinical Trials Directive 2001/20/EC”, Version 2, 23/03/2010

//////////Regulatory Approval Pathways,  EU vs US


As of September 2015, updated Requirements apply to the Application of a CEP!

As of September 2015, updated Requirements apply to the Application of a CEP!

The EDQM recently revised its certification policy. Read more here about what you now need to consider when applying for a Certificate of Suitability (CEP).–updated-Requirements-apply-to-the-Application-of-a-CEP!_9159,9255,9299,9300,S-WKS_n.html

The EDQM recently published a revised version of its certification policy document titled “Content of the dossier for chemical purity and microbiological quality“. The revision takes into account the new regulatory developments in Europe that are reflected in many revised and, to some extent, new guidelines of the EMA, ICH as well as in some revised general chapters and monographs of the European Pharmacopoeia (see the summary of these guidance documents under “References” at the end of the policy document).

The aim of the policy document is to provide CEP applicants with a guideline for preparing the authorisation dossier and for compiling all the documents required for this. The dossier is to be divided into 3 modules:

  • Module 1: The authorisation history of the products is to be described which contain the active ingredient for which a CEP application is submitted. The following declarations are also to be submitted:

    – a declaration of GMP conformity from all manufacturers involved in the manufacture of intermediate products and the final active ingredient,

    – a declaration from these manufacturers that they are willing to be inspected before and after being granted a certificate of suitability,

    – a declaration of the CEP applicant/holder about the use/non-use of material of human or animal origin. In cases where such material is used, compliance with the provisions of the EDQM Guideline “Content of the dossier for a substance for TSE risk assessment (PA/PH/CEP (06) 2)” should be demonstrated.

    – a commitment to provide the EDQM, upon request, with samples of the final active ingredient and/or its impurities,

    – a declaration to acknowledge the provisions of the Certification procedure and to agree to the exchange of assessment reports between the national competent authorities of the European Member States as well as the EMA experts.

  • Module 2: Part of this module (analogous to the CTD structure) is the Quality Overall Summary (QOS). The EDQM published a ready-to-use Word template for this. The template can be accessed on the EDQM website “Submit a new application” which contains the most important facts regarding the submission of a new application for a CEP together with links for the relevant documents. With the description of the active ingredient in the QOS, evidence must be provided that the pharmacopoeia monograph is suitable to control the quality of the active ingredient, particularly with regard to the impurity profile of the substance. Plausible justification is important for the cases where testing for possible impurities is omitted.
  • Module 3: Also this Module reflects the CTD structure, i.e. the content of subchapter 3.2.S.1 to 3.2.S.7 with further subdivisions corresponds to the content of a standard authorisation application for a medicinal product. Here are some examples of important points that must be considered in light of the regulatory developments:

    – A CEP that covers different grades of active ingredient (different physical properties, such as particle size or certain polymorphic forms) cannot be issued if these grades also have different limits for impurities and if different analytical methods of determination are required for their control. A CEP for different grades of freedom from pyrogens or bacterial endotoxins is only possible when the relevant monograph foresees this. Otherwise, separate applications must be submitted for grades of the active ingredient that do and do not contain pyrogens or endotoxins (“General properties“; 3.2.S.1.3).

    – Different production sites and manufacturing processes may only be described in one and the same application if it can be proven in a plausible manner that the quality (specifications and impurity profiles) of the relevant intermediate products and the final active ingredient is not significantly changed. Reprocessing steps are to be clearly described; reworking is not normally accepted (“Description of the manufacturing process and process controls“; 3.2.S.2.2).

    – The selection of the starting material is to be justified as per the regulations of ICH Q11 and the EMA Reflection Pager on Starting Materials (EMA/448443/2014). Single step synthesis is generally not accepted unless the starting material itself has a CEP (see EDQM Guideline “Use of a CEP to describe a starting material in an application for another CEP“). Testing for impurities including solvents, catalysts and reactants and absence of a possible carryover into the final product is to be described (“Control of materials“; 3.2.S.2.3).

    – Validation data for manufacturing sterile substances is to be submitted; the complete validation data (protocols and reports) is to be presented for the sterilisation process. Part 2 of the EU GMP guidelines applies to the manufacture of the active ingredient until immediately before the sterilisation stage; sterilisation and aseptic processing should be carried out according to Annex 1 of the guideline (“Process validation and/or evaluation” 3.2.S.2.5).

    – Testing for all kinds of impurities (reagents, catalysts, solvents, by-products etc.) and their potential sources are to be described, particularly if the monograph does not contain suitable test methods. Analytical data and a minimum of significant validation data (incl. LOD/LOQ values) are to be presented (“Impurities“; 3.2.S.3.2).

    – Data from formal stability studies are not normally required for active ingredients. However, when a retest period is requested to be mentioned on the certificate, these data must be collected and submitted as per the guideline “Stability testing of existing active substances and related finished products” and its Annexes (“Stability“; 3.2.S.7).

Overall the provisions of the new certification policy document are rather extensive. As mentioned at the start, the pharmacopoeia authority has reacted to the increased requirements in the newly published and revised ICH and EU guidelines. The policy document is now applicable with no transition period, which means CEP applicants who submitted their application without knowing about this document may receive from the EDQM a particularly long list of deficiencies along with the request to submit the relevant information required.

EU: New GMP Implementing Act published

The EU Commission has published a new public consultation on an Implementing Act on GMP principles and guidelines for medicinal products for human use.

The EU Commission has published a new public consultation on an Implementing Act on Principles and guidelines on good manufacturing practices for medicinal products for human use.,9232,10335,Z-QAMPP_n.html

The reason is that once Regulation (EU) No 536/2014 on clinical trials becomes applicable, manufacture and import of Investigational Medicinal Products (IMPs) for the use in clinical trials carried out under that Regulation cannot follow GMP for IMPs set out in Directive 2003/94/EC. They then have to be manufactured or imported under regulations laid down by the Delegated Act or other specified regulation. It is therefore necessary that Directive 2003/94/EC is revised by a new Implementing Directive on principles and guidelines of good manufacturing practice for medicinal products for human use (without IMPs).

The EU Commission states that because “good manufacturing practice for medicinal products for human use already exists and is generally well-functioning, there is no need to reinvent the wheel”. So the GMP related consultation documents carry over elements set out in Directive 2003/94/EC relating to medicinal products for human use.  GMPs for advanced therapy medicinal products will be introduced with a new provision.

How to become a QP for Europe

Both the ECA and the European QP Association are often contacted by people who would like to become a Qualified Person in a Member State of the European Union or outside the EU to release products for the EU market.

Both the ECA Academy and the European Qualified Person Association (EQPA) are often contacted by people who would like to become a Qualified Person (QP according the EU Directives) in a Member State of the European Union or outside the EU to release products for the EU market. Questions are for example:

  • “Can I become a QP and live and work outside the EU?”
  • “I work for an American company that would like to export medicinal product to the EU. How can we hire a QP here in the U.S.?”
  • “I am an Irish Citizen living and working in Australia. I am thinking of studying a course by distance learning, which also meets the requirement for persons seeking to become a QP. Is that possible?”
  • “I’m a Spanish pharmacist working in Switzerland. I’m wondering how to proceed to become a Qualified Person. Which is the training that I have to follow to become QP in Europe?”

Unfortunately this is not as easy as one would think. To become a QP there are a few things that need to be considered:

1. The European Qualified Person is linked to a European Manufacturing authorization and licence (EU/ECC).

2. A QP is registered by the authority of the respective EU member state (or MRA-State). The requirements might differ from member state to member state.

In Article 49 of Directive 2001/83 (for veterinary medicinal products, please read Article 53 of Directive 2001/82), the qualification level as well as the necessary experience of a QP is defined:

(2) “A qualified person shall be in possession of a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course of study, or a course recognized as equivalent by the Member State concerned, extending over a period of at least four years of theoretical and practical study in one of the following scientific disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology (…). The course shall include theoretical and practical study bearing upon at least the following basic subjects:

  • Applied physics
  • General and inorganic chemistry
  • Organic chemistry
  • Analytical chemistry
  • Pharmaceutical chemistry including analysis of medicinal products
  • General and applied biochemistry (medical)
  • Physiology
  • Microbiology
  • Pharmacology
  • Pharmaceutical technology
  • Toxicology
  • Pharmacognosy (study of the composition and effects of the natural active substances of plant and animal origin).

In so far as certain diplomas, certificates or other evidence of formal qualifications mentioned in the first subparagraph do not fulfil the criteria laid down in this paragraph, the competent authority of the Member State shall ensure that the person concerned provides evidence of adequate knowledge of the subjects involved.”

So, to act as a QP as defined in the EU Directives, you have to work in an EU Member State and fulfil the requirements of the directives. These requirements have to be transferred to national law in each EU Member State. However, there are a number of differences in the EU Member States due to the fact that each Member can implement the directives into national law with slight modifications.

More information can also be found on the website of the European QP Association.,9336,Z-QAMPP_n.html


How to document a Product Transfer? Example templates!

All participants of the GMP training course “GMP-compliant Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects. Read more.

According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.

As a participant of the GMP education course “GMP-compliant Product Transfer” in Prague, from 20-22 October 2015 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.

Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the EU/US Variation Guidelines, are also part of the Guideline Manager CD. Due to copyright reasons, this CD is not available for purchase and can only be handed out to participants of the transfer course.,Z-PEM_n.html


ECA and PQG publish Chapter 6 of the interpretation of the ECA and PQG publish Chapter 6 of the interpretation of the EU GDP Guideline

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the interpretation of different chapters of the EU GDP Guideline. Now the group has finalized the work on chapter 6 – Complaints, Returns, Suspected Falsified Medicinal Products & Medicinal Product Recalls. Read more about the GDP Guidance Chapter 6.,S-GDP_n.html

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the interpretation of different chapters of the EU GDP Guideline. The interpretation of five chapters have been published already. The following 5 Guidance chapters on the EU GDP Guideline are available:

Chapter 1: Quality Management
Chapter 9: Transportation (also contains a template for a Technical Agreement)
Chapter 7: Outsourced Activities
Chapter 2: Personnel
Chapter 5: Operations

Now the group has finalized the work on chapter 6 – Complaints, Returns, Suspected Falsified Medicinal Products & Medicinal Product Recalls. Chapter 6 of the EU GDP Guideline requires that all complaints, returns, suspected falsified medicinal products and recalls must be recorded and handled carefully according to written procedures. Some returned medicinal products might be released for resale. The handling should be performed only after an assessment of the returned medicinal products. The approval should be made by the Responsible Person (RP). Also complaints must be handled based on a written procedure and all details of each complaint must be recorded. Finally, the identification and handling of Falisified Medicinal Products are also defined in chapter 6. The ECA/PQG Guidance document provides information on how to implement the requirements.

You will find chapter 6 and all other GDP Guidance chapters in the members area of the GDP Group Webpage. Membership is available at no costs

New EU GMP Annex 15 Revision published – Valid as of 1 October 2015



In February 2014 the draft for the revision of Annex 15 was published. Compared with the currently valid version the changes were partly significant. Now the draft was published as final document and will be valid as of 1 October 2015. Read more about the Changes in Annex 15.—Valid-as-of-1-October-2015_9184,9266,9185,9322,Z-QAMPP_n.html

In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 “Revision of the EU GMP Annex 15 for Qualification and Validation published“). Compared with the currently valid version the changes were significant in some parts (see also the GMP-News from 21 March 2014 “Detailed Analysis of Annex 15 Draft“. Now the draft was published as final document and will be valid as of 1 October 2015.

What will change? Following you will find an overview about the changes.

With 16 pages the document is much more comprehensive than the current version (11 pages). In the section “principles” it is stated that the new EU GMP Annex 15 may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II”

Life cycles build the centre of the new Annex 15, whether with regard to the product or to the process, whether with regard to equipment and the process validation itself. A special emphasis is on risk management which is mentioned in several sections in the guideline instead of being mentioned in one section only on risk assessment.

The new Annex 15 now specifically excludes a retrospective validation.

Validation Master Plan
The content of the validation master plan (VMP) has been extended. Deviation management is also supposed to be described in the VMP in the future, just as well as the standards for the development of acceptance criteria and the organisational structure. Compared to the draft version the mention of an “ongoing validation strategy” has been deleted. The request for naming the resources has also been omitted compared to the draft.

The possibility to combine qualification documents (e.g. IQ and OQ as IOQ) is explicitly mentioned. It is also foreseen to include manufacturer documents. Fortunately there is the possibility of conditional releases in the area of qualification. The final document contains a requirement to establish user requirements and/or functional specifications as a starting point of a qualification. The DQ is now the second step in a qualification. Additional new requirements are the Factory Acceptance Test (FAT) and the Site Acceptance Test (SAT). Especially for equipment with new or complex technology a FAT “may” be conducted. Compared to the draft this is a less strict requirement. In the draft document it was stated that a FAT “should” be conducted. If appropriate and assessed, tests and documentation reviews as part of the FAT can be taken over in other steps without repeating them in the IQ/OQ. This is a very helpful definition.

With regard to the PQ it is now also explicitly mentioned that (in certain cases) it can be combined with the OQ or the process validation. In difference to the draft it is stated that IQ, OQ and PQ “should” be conducted.

The chapter “Requalification” is new. Unfortunately the sub-chapter on established (in-use) equipment qualification has been completely omitted.
Process Validation
The options with regard to process validation have been extended. The previous “traditional” approach is still mentioned as a possibility, though – also with the determination of 3 validation batches. For a 3 batch validation further data from following batches may be necessary according to an “ongoing process verification”. The possibility of a “continuous process verification” as described in ICH Q8, and a hybrid approach as a mix of the before mentioned two approaches is new. This is a clear difference to the US FDA Process Validation Guidance where only one approach is mentioned. According to the final EU GMP Annex 15 a “bracketing” approach can be used with respect to the number of runs, strength, batch size, packaging sizes and types. This is already known from the US.

As part of the “ongoing process verification” the product quality should be monitored during the product life cycle to show that the “state of control” is fulfilled and that trends are assessed. This is also known as “Continued Process Verification” from the US. The “ongoing process verification” should be based and reported according to a protocol or equivalent documents, latter is new compared to the draft. Completely omitted has been the subject of a (regular) revalidation.

The chapters “Transport Verification”, “Packaging Validation” and “Qualification of Utilities” as well as a separate chapter on “Validation of Analytical Methods” are new.  Compared to the draft the new final document now addresses also the qualification of equipment for secondary packaging.

Cleaning Validation
The chapter Cleaning Validation comprises clear changes. The number of subitems is more than double now. Fortunately it is possible now to group equipment if this grouping is justified accordingly. The acceptance criterion “visibly clean” as single acceptance criterion is designated as not acceptable. Limits for the carryover of contaminations are supposed to be based on a toxicological evaluation. There is a reference to the EMA Guideline on Shared Facilities (see GMP News from 21 November 2014 “Shared and Dedicated Facilities: EMA publishes final Guideline on Setting health based exposure limits (PDEs)“. The so far common acceptance criteria 1/1000-Dose or 10 ppm are not mentioned. As part of the cleaning validation “dirty und clean-hold times” should be defined. The request from the draft to use the last rinse water as a sample in the application of rinsing methods has been omitted. Recovery rates should be determined. Interestingly the number of validation runs is supposed to be determined risk based. When producing clinical trial samples a cleaning verification could replace a cleaning validation.

In the chapter Change Control it is defined that an efficiency control is supposed to follow a change. This is an adaption to chapter 1, part I of the EU GMP Guide.

The glossary contains new terms.

The revision is quite comprehensive. Influences from the ICH Guides ICH Q8, Q9 and Q10 can be clearly noticed. This makes the document more modern, and it is more adapted to the current state of science and technology. The addressing of API manufacturer is somewhat irritating. Although the new Annex 15 comprises clear changes it is not supposed to cause new requirements in the area of APIs. But how is that supposed to work?

The statement that Process Validation is a life cycle is comparable to the FDA view.

The clear focus on user requirements in the area of qualification will also have an impact on equipment suppliers. Process validation will become a difficult task in the future. With 3 different approaches there are clear differences to the US. However, the ongoing process verification means additional effort and is now comparable to the US requirements.

Transport verification, the qualification of utilities as well as the validation of analytical methods are not new in the GMP enviroment. However, the topic packaging validation was not the main focus so far. This probably means additional effort for some companies.

The new Annex will result in considerable changes in the area of cleaning validation. A lot has fortunately been adapted to the current state of technology. However, the strong focus on toxicological evaluations as acceptance criteria with regard to existing products will certainly cause uncertainties.

Altogether there are plenty of new requirements which, however, partly only show the state of technology. Due to the (necessary) integration of ICH Q8-Q11 and the life cycle approach the new Annex 15 is now more comprehensive, but unfortunately also more vague. A close coordination with the FDA Guideline on process validation would have been desirable.

Please find the new EU GMP Annex 15 on the EU Commission Webpage

The new EU GMP Annex 15 will be covered at two ECA events. On 22/23 April the ECA offers the seminar “The new FDA/EU Approach to Process Validation” in Hamburg. And, at the 6th European GMP Conference on 9/10 June in Heidelberg the EU GMP Annex and the consequences will be discussed in a dedicated session.

Gmp Guideline Eu Gmp Annex 15 Qualification And Validation

Gmp guideline eu gmp annex 15: qualification and validation, Eu gmp annex 15: qualification and validation: internet:–v4an15.pdf: origin/publisher: european commission. Eu gmp guide – annex 15 qualification & validation draft, White paper eu gmp guide-annex 15 qualification & validation draft released © 2014 pharmout. this document has been prepared solely for the use of pharmout and its. Guideline: eu gmp annex 15: qualification and validation, Regelwerke zu good manufacturing practices ändern sich. mit dem gmp-navigator bleiben sie auf dem laufenden. gmp-navigator.Definition of DQ (EU GMP Guideline, Annex 15) - Design qualification

New draft gmp guideline – european commission, 4 qualification and validation principle this annex describes the principles of qualification and validation which are applicable to the facilities, equipment. European medicines agency – gmp/gdp compliance – questions, European union (eu) gmp guide part i: basic requirements for medicinal products: chapter 3: equipment. back to top. 1. should metal detectors be used routinely in. Gmp news – good manufacturing practices – gmp newsletter, Gmp news about eu, ema, europe, us fda, pharmaceutical quality, ich, who, pic/s..

Definition of DQ (EU GMP Guideline, Annex 15) - Design qualification
Definition of DQ (EU GMP Guideline, Annex 15) – Design qualification

Click here to get More Info About Gmp Guideline Eu Gmp Annex 15 Qualification And Validation


Overview about API manufacturing for the European market



EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Please read more about the API registrations in EudraGMDP.,S-WKS_n.html

EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Although the database is still not complete (not all competent authorities in Europe have established a system to make sure that all registration data will be entered into EudraGMDP in a timely manner) the current information is already very interesting.

Currently (as per 19 March 2015) the database counts 3.275 API manufacturing sites, importers or distributors located outside Europe. On the other side 936 API manufacturing sites, importers or distributors are located in EEA countries (EU Member states plus Norway, Liechtenstein and Iceland). According to the database India counts for 1.473 companies and China for 1102 companies. The USA only counts for 198 and Switzerland for 71 companies. Within the EEA the United Kingdom counts 138 countries while Italy counts for 71and Spain for 192. Still work is needed to put all information into the database as France does not have a single entry and Germany only 3.

But the database is a good source to find some basic information about API manufacturers, importers and distributors. Each company registration file is available and allows to check the date of issue of the registration and the products concerned. However, it must be stated that a registration does not mean that an inspection took place. A registration will be granted also without a prior inspection at the company.

Source: API Registration in EudraGMDP


New information about CEPs and inspections published by EDQM….see about Telangana, India

The European Directorate for the Quality of Medicines & Healthcare (EDQM) has published new information about the CEP procedure and its related inspections. Please read more about he latest updates from EDQM.,S-WKS_n.html

The European Directorate for the Quality of Medicines & Healthcare (EDQM) has published new information about the CEP procedure and its related inspections.

1) Costs of inspections

The EDQM has published a new document which describes the inspection costs. The EDQM document PA/PH/CEP (12) 28 1R refers to a table of fees and inspection costs. The costs for the inspection as well as for the travel will be invoiced prior to the inspection. For a three day inspection, for example, the fee is 5000,- Euro. If the facility is located in Asia a flat rate of 6000,- Euro will be charged to cover the travel costs, food and accommodation for the inspector. The travel costs are less when the facility is located in Europe (800,- Euro) and elsewhere (4500,- Euro). The CEP inspection fee table can be found here.

2) New Indian State has impact on CEP holders

The Indian government created a new state on 2nd June 2014 which is called Telangana. The EDQM reminds holders of CEPs and applicants for CEPs that it is their responsibility to update their CEP applications. Many of the addresses mentioned on CEPs and in CEP applications which are currently listed as being in Andhra Pradesh are now in this new state of Telangana. The new address details, as well as an updated section 3.2.S.2.1 should be submitted to EDQM. This should be done until 31 August 2015.

    1. Map of telangana

Generic drugs in the EU

Process of reviewing and assessing the dossier to support a medicinal product in view of its marketing (also called licensing, registration, approval, etc.), obviously finalized by granting of a document also called marketing authorization (equivalent: product license). This process is performed within a legislative framework which defines the requirements necessary for application to the concerned (competent) regulatory authority, details on the assessment procedure (based on quality, efficacy and safety criteria) and the grounds for approval or rejection of the application, and also the circumstances where a marketing authorization already granted may be withdrawn, suspended or revoked.NOTE [1]
The application dossier for marketing authorization is called New Drug Application (NDA) in the USA or Marketing Authorization Application (MAA) in the European Union and other countries, or simply registration dossier. Basically, this consists of a dossier with data proving that the drug has quality, efficacy and safety properties suitable for the intended use, additional administrative documents, samples of finished product or related substances and reagents necessary to perform analyzes of finished product as described in that dossier. The content and format of the dossier must follow rules as defined by the competent authorities. For example, since year 2003, the authorities in the United States, the European Union and Japan ask for the Common Technical Document (CTD) format, and more recently, its electronic version – the electronic Common Technical Document (eCTD).

Marketing Authorisation

The application is filed with the competent drug regulatory authority in the concerned country, which can be either an independent regulatory body or a specialized department in the ministry of health.
In accordance with local legislation, the resulting document allowing to the applicant to market the product may be more detailed (in addition to data identifying the product and its holder it may contain addresses of all manufacturing sites, appended labeling, artwork of packaging components, etc.) until a one-page document called certificate of registration (and containing minimal data identifying the product and its source).
Many generic drugs are now being prescribed and the trend is increasing. For example, in Austria, the number of all generics prescriptions has more than doubled from 11% in 2000 to 23% in 2010. However, many myths and questions about generic drugs remain and information may be difficult to come by. It is therefore not surprising, as we have discovered in recent years, that even physicians and pharmacists are not always fully up to date in their understanding of generic drugs. Some of their questions centre on issues such as: are generic drugs really as good as the original; are we really dealing with an adequately tested, high quality medicinal product.
Today, generic drugs present an equally well-tolerated and efficacious alternative to established medicinal products, which contain well-known, rigorously tested active ingredients. An established originator product undergoes expensive and protracted development (up to 15 years) with inherently high preclinical and clinical research costs in order to be given market approval. The development of generic drugs, on the other hand, is relatively quick and inexpensive, which allows generic drugs to be sold at a distinctly cheaper price. This is due to the waiving of new preclinical and clinical studies, aside from some bioequivalence studies. Their lower price however should not be equated with ‘cheap quality’. In fact, generic medicines undergo the same strict scrutiny by the European or national medicines authorities as reference products.
 This marketing authorisation validates the safety, efficacy, and quality of a generic drug.

What makes a generic medicinal product generic?

The definition, according to Austrian drug law/the Medicinal Products Act as well as to EU Directive 2001/83/EC, is that a generic medicinal product ‘is a product which has the same qualitative’, i.e. kind of active substance, ‘and quantitative’, i.e. amount of active substance, ‘composition as the reference medicinal product’. For the sake of simplicity, the reference product is often also referred to as the originator. The different salts, esters, or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in their safety and/or efficacy properties. In these cases, the manufacturer of a generic drug has to submit further proof of efficacy and safety.
The pharmaceutical form, which means the distinct way a product is to be administered, of the generic medicinal product has to be the same as for the reference medicinal product [1]. However, remarkably the various types of immediate release oral pharmaceutical forms, e.g. tablets, capsules and dragées, are considered to be one and the same pharmaceutical form. A patient prescribed with a particular medicinal product may therefore be prescribed either a film-coated tablet or a capsule of the same drug by his physician. This in itself does not pose a problem, as the galenic formulation may indeed be different, but the impact on the safety and efficacy profile of the whole product has been judged to be comparable during the approval procedure.

Are different compositions possible?

Differences in composition between the generic and reference medicinal product are possible, but only regarding the excipients, e.g. bulking agents, colouring agents; and not for the active substances. For example, corn starch may be used instead of lactose as an excipient. However, it has to be demonstrated by the applicant of the generic drug that these differences in composition do not influence the therapeutic efficacy and safety or how the drug is absorbed, distributed, metabolised or eliminated by the body, i.e. the drug’s pharmacokinetics must also remain more or less the same.
Bioavailability or bioequivalence trials need to be conducted in order to demonstrate the equivalence between the generic medicinal product and the reference medicinal product. Differences in the manufacturing process compared to the originator are allowed, but the same strict general quality criteria, e.g. controlled production under good manufacturing practice (GMP), apply to the production of the generic medicinal product as well as for the reference product.
Also a medicinal product can only be considered as the reference product if it has been granted market approval in at least one Member State of the European Economic Area. However, only the so-called originator can serve as the reference product in bioequivalence testing, but never another generic drug, as this would otherwise mean the allowance of a copy of a copy.

How soon can generic medicinal products appear on the market?

The applicant needs to provide proof that the originator product has been authorised for at least eight years, or that the originator company has issued a written informed consent stating that the generics company is permitted to apply for its generic drugs sooner. As a rule however, the earliest a generic medicinal product is allowed to go on sale is 10 years after the first European originator is granted marketing authorisation. This 10-year market exclusivity can be extended by an additional year if, during the first eight years, the marketing authorisation holder of the originator obtains an additional authorisation for one or more new relevant therapeutic indications [2]. Figure 1 shows the ‘8+2 (+1) Formula’ applicable to generic medicinal products entering the market.
Some originators, however, hold patents—in some cases up to 1,000 patents for one single product were found—which can further postpone the launch of a generic drug. Such delay in market access is therefore possible, even if the marketing authorisation has already been granted to the generic drug. Notably, some misuse of patent strategies was described in the final report of the 2009 sector inquiry of the European Commission for Competition [3]. In a sample of 219 molecules from 2000 to 2007 there were reportedly 1,300 patent-related out-of-court disputes related to the launch of a generics.
The number of patent litigations brought to court totalled nearly 700 cases in these seven years and the number of cases increased by a factor of four between 2000 and 2007. The report reached the conclusion that the behaviour and practices of originators contribute to generics delay as well as to difficulties in innovation itself because originators may even block each other.

What is a bioequivalence study?

Bioequivalence studies are often the demanded basis for granting marketing authorisation for a generic medicinal product. They are clinical studies conducted in accordance with Austrian drug law as well as to EU Directive 2001/20/EC and provide data to demonstrate bioequivalence between a test product, i.e. the generic medicinal product, and a reference product, i.e. the originator.
The rate and extent of absorption of the medicinal products and therefore the bioavailability of the active substance(s) are determined. It is a widely accepted regulatory assumption, even sometimes challenged by generics disputants, that equivalent plasma concentration time curves represent equivalent efficacy and safety. Therefore, if bioequivalence can be shown after the administration of the same molar dose, equivalence or assumption of so-called essential similarity of the two products in terms of efficacy and safety can be concluded.

What are the rules for conducting bioequivalence studies?

How exactly a bioequivalence study has to be conducted, and which requirements need to be taken into consideration, is laid out in detail in the European bioequivalence guideline, the revised version of which came into effect mid-2010. The guideline clearly specifies the requirements for the design, conduct, and evaluation of bioequivalence studies for all EU countries. Since 2001, when the first bioequivalence guideline was published, many additional aspects were identified which needed to be amended and improved. Minor issues were addressed in interim question and answer documents.
After a three-year preparation period, the comprehensively revised version of the guideline came into effect in August 2010. The comments and suggestions of over 50 expert organisations and associations were worked into the 22 draft versions. The revised version therefore now reflects the most up-to-date state of knowledge, which is essential in issuing harmonised and standardised marketing authorisations across Europe.
The aim of the guideline was to do away with the ambiguities of the past, which often led to lengthy discussions and differences in professional opinion between the countries and competent authorities of the EU. This also ensures the safety and efficacy of all generic drugs being granted marketing authorisation.

Are bioequivalence studies only used in the development of generic drugs?

Since the task of bioequivalence studies is to detect differences between formulations or pharmaceutical forms, they are indeed not only used as a basis for the licensing of generic medicinal products. In fact, originators may also use bioequivalence studies during their own development since the formulation first used in clinical trials is often not the same which later goes into large-scale market production. Bioequivalence studies are used in these cases to allow bridging of the results obtained in the clinical trials. The same principles in study conduct, data evaluation, and assessment of results by the authority are applied in such originator studies as in the above-described studies for generic drugs. Remarkably, essential similarity between an originator small-scale clinical trial product and a large-scale originator product later to be for sale has never been put in question by anyone. Considering media coverage sometimes casts massive doubt about generics and the way they are authorised, obviously there seems to be an unfounded contrast in the perception dependent on who—the originator company or the generics company—makes use of the bio – equivalence concept for the authorisation of one of their products. Assuming that the bioequivalence concept is valid and trustworthy for authorisation of a new originator product, the same should be applied to the authorisation of a generic drug.

Is the manufacturing quality the same for generic and originator products?

The same quality requirements apply to the manufacturing of generic drugs as for any other medicinal product. Production has to be performed in accordance with GMP and is strictly controlled by evaluating the manufacturing data and by inspections performed not only in Austria and the EU, but also all over the world including countries such as India and South Africa. As for any other medicinal product, quality deficiencies in individual batches are theoretically possible and therefore the Austrian Federal Office for Safety in Health Care as well as the other competent EU authorities closely monitor the quality of all authorised medicinal products on the market. This is achieved by the legal obligation of authorisation holders to inform the authority about every out-of-specification results or other problems in manufacturing and an additional quality-defect notification system involving all healthcare professionals. This guarantees that only high quality medicinal products are available, regardless of whether these products are originators or generics.

When is a generic drug granted market authorisation?

An Austrian or an EU marketing authorisation is only issued when the pharmacokinetic parameters of the generic drug are comparable to those of the reference product and bioequivalence has been successfully demonstrated.
Furthermore, the overall benefits of the generic medicine need to outweigh its risks (positive risk–benefit ratio) and its excipients and the manufacturing process must have been demonstrated to not negatively influence its safety and efficacy.
Last but not least, all internationally relevant quality standards and legal requirements have to be fulfilled before marketing authorisation can be granted.

Procedures for obtaining a marketing authorization

Authorization processes follow either a purely national procedure, with rules and requirements as per national legislation in force, as it occurs in most of countries worldwide, or should follow a centrally approval or a mutual recognition or decentralized procedure within the European Union.

Types of applications

The type of application may vary according to status of the active ingredient.
Thus, if the application concerns a new active ingredient (new active substance, new chemical entity, new molecular entity), one talks about a full application.
Once a new active ingredient authorized, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations (changes to the existing marketing authorization) and extensions shall also be granted an authorization or be included in the initial marketing authorization, being subject of an abridged application.NOTE [2]
Special consideration is to be given to application for authorization of biological products and biotechnology products,[1] homeopathic products, herbal drugs, radionuclide generators, kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals; in such instances, requirements are specific, in the meaning that they are special, more or less detailed, as per the nature of active ingredient.

Validity of marketing authorizations

In most countries, a marketing authorization is valid for a period of 5 years. After this period, one should apply for renewal of the marketing authorization, usually by providing minimal data proving that quality, efficacy and safety characteristics are maintained and the risk-benefit ratio of the medicinal product is still favourable. However, in the European Union, after one renewal, the marketing authorization shall remain valid for an unlimited period, unless the competent regulatory authority decides otherwise.NOTE [3]
If the marketing authorization is not renewed in a due time as requested by the local legislation, in order to maintain the pharmaceutical product on a market, one can apply for re-authorization (re-registration). In such situations, the applicant may be requested to submit the whole items necessary for a full application.
Marketing authorization may be withdrawn, suspended, revoked or varied by regulatory authorities if under normal conditions of use the benefit over risk ratio is no more favorable, the product is harmful, or if it lacks therapeutic efficacy; also, one of the above actions can be taken if the qualitative and quantitative composition or other qualitative aspects (control) are not as currently declared.
Marketing authorization may be also withdrawn, suspended or revoked if the marketing authorization holder or its representative does not fulfill other legal or regulatory obligations necessary to maintaining of product on the market, as per the legislation in force.
Also, the marketing authorization is withdrawn in the EU if the product is not placed on the market within next 3 consecutive years after granting of authorization or if it is no more marketed for 3 consecutive years (so-called “sunset clause”).NOTE [4]


  1. Jump up to:a b
  2. Jump up^ Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Official Journal of the European Union, L 311, 28.11.2001, p. 67.
  3. Jump up^ Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. L 136, 30.4.2004, p. 34.
  4. Jump up^ CMD(h) Agreement on Sunset Clause and its application to MAs granted in more than one Member State. Co-ordination Group for Mutual Recognition and Decentralised Procedures -Human, December 2006.
  1. European Medicines Agency. CPMP/EWP/QWP/1401/98 Rev.1. Guide line on the investigation on bioequivalence. Available from:
  2. European Commission. Guidance on elements required to support the significant clinical benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended (11 years) marketing protection period, 2007. Available from:
  3. European Commission Competition, EU Sector inquiry, 8 July 2009. Available from:
  4. Tschabitscher D, Platzer P, Baumgärtel C, Müllner M. Generic drugs: quality, efficacy, safety and interchangeability. Wien Klin Wochenschr. 2008;120:63-9.
  5. American Medical Association. Summaries and recommendations of Council on Scientific Affairs Reports. Generic drugs (CSA Rep 6, A-02). 2002 Annual Meeting of the American Medical Association. 2002:13-4.
  6. Henney JE. Review of generic bioequivalence studies from the food and drug administration. JAMA. 1999;282:1995.
  7. Nwakama PE. Generic drug products demonstrate small differences in bioavailability relative to brand name counterparts: review of approved ANDAs, FDA. 2005.
  8. Davit BM, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the FDA. Ann Pharmacother. 2009 Oct; 43(10):1583-97.
  9. Statement of the Austrian Society of Cardiology (ÖKG) regarding Clopidogrel-Generics. 2010. Available from:
  10. Consensus statement of Austrian Society of Biologic Psychiatry (ÖGBP), Generics and originators in psychiatry, 2008. Available from:

Intellectual Property (IP) Value Realization

IP-driven companies thoroughly and vigorously develop a Technology Value Realization (IP Commercialization) process to a level of sophistication such that they can predict with a reasonably high degree of accuracy the market success for their emerging technologies. This process links the stages of moving a technology with product potential to patent procurement/ management. In the four phases of technology commercialization, there are parallel patent value realization activities.

Bringing Patent Protected Technology to Market
The process begins in the Research & Development (R&D) labs where technology with product potential is identified. It is at this early point that the linkage with the patent process is formed.
Commercialization Process Patent Process
  I. Technology Analysis Process   I. Patent Search
  • Starts with an analysis of the technology followed by the development of a draft Technical Product Description
  • Patent searches are done for prior art
  • Provisional patents may be filed
  II. Market Opportunity Identification   II. Patent Application
  • Market opportunity identification
  • Competitive analysis
  • Draft Business Case
  • Final Technical Product Description
  • Initial patent value determination is made
  • Patent application is registered with the Patent and Trademark offices of the US (and other countries) for value added features
  • Patent Issued (or rejected)
  III. Market Actualization Planning   III. Patent Profit Planning
  • Most effective method(s) for value realization/commercialization are determined
  • Develop licensing strategies and Patent Licensing Agreements (PLAs)
  IV. Implementation   IV. Patent Management
  • Commercialization and appoint of a Product Manager (or market manager) to transition the technology into implementation and bring it to market
  • Associated patent(s) are then moved into Patent Management

Tuesday, 27 January 2015


The Paris Convention, signed in 1883 was one of the first IP treaties and now has over 170 signatory countries of which the US is one. The fundamental benefit of this treaty is that the filing date of a patent application filed in any one of the convention countries can serve as the priority date for patent applications filed within one year in any other member country. There are other treaties with similar reciprocal priority rights. The US, for example, has one with Taiwan.

The Paris Convention
As we discussed, the Paris Convention is an international treaty that allows applicants to file a first application in their home country. That application is referred to as a priority document or filing, and the date it is filed is called the priority date.
The priority filing starts a 12-month period within which a further application called a Paris Convention application (or a direct application claiming priority) can be filed elsewhere, claiming Paris Convention priority back to the priority date. To the extent that the content of the Paris Convention application is disclosed in the earlier priority document, it will be backdated to the priority date.
The advantages of using the Paris Convention are well known to those familiar with the patent process. The 12-month convention period lets the applicant seek funding, perform market research and turn an idea into a commercial product. All of these can be done following a single filing without risking a loss of rights in other countries.
If the Paris Convention didn’t exist, applicants would need to coordinate simultaneous filing in all countries that are of potential interest at the very start of the process. This would be complicated and costly, bearing in mind the need for translations in many countries.
– See more at:

The Paris Convention
As we discussed, the Paris Convention is an international treaty that allows applicants to file a first application in their home country. That application is referred to as a priority document or filing, and the date it is filed is called the priority date.
The priority filing starts a 12-month period within which a further application called a Paris Convention application (or a direct application claiming priority) can be filed elsewhere, claiming Paris Convention priority back to the priority date. To the extent that the content of the Paris Convention application is disclosed in the earlier priority document, it will be backdated to the priority date.
The advantages of using the Paris Convention are well known to those familiar with the patent process. The 12-month convention period lets the applicant seek funding, perform market research and turn an idea into a commercial product. All of these can be done following a single filing without risking a loss of rights in other countries.
If the Paris Convention didn’t exist, applicants would need to coordinate simultaneous filing in all countries that are of potential interest at the very start of the process. This would be complicated and costly, bearing in mind the need for translations in many countries.
– See more at:
The Paris Convention

Marketing Authorisation in Europe

European Commission logo

Authorisation Procedures for medicinal products

Procedures for evaluating medicinal products and granting marketing authorisation

The European system for the authorisation of medicinal products for human and animal use was introduced in January 1995 with the objective of ensuring that safe, effective and high quality medicines could quickly be made available to citizens across the European Union.
The European system offers several routes for the authorisation of medicinal products:
  • The centralised procedure, which is compulsory for products derived from biotechnology, for orphan medicinal products and for medicinal products for human use which contain an active substance authorised in the Community after 20 May 2004 (date of entry into force of Regulation (EC) No 726/2004) and which are intended for the treatment of AIDS, cancer, neurodegenerative disorders or diabetes. The centralised procedure is also mandatory for veterinary medicinal products intended primarily for use as performance enhancers in order to promote growth or to increase yields from treated animals.
    Applications for the centralised procedure are made directly to the European Medicines Agency (EMA) and lead to the granting of a European marketing authorisation by the Commission which is binding in all Member States.
  • The mutual recognition procedure, which is applicable to the majority of conventional medicinal products, is based on the principle of recognition of an already existing national marketing authorisation by one or more Member States.
  • The decentralised procedure, which was introduced with the legislative review of 2004, is also applicable to the majority of conventional medicinal products. Through this procedure an application for the marketing authorisation of a medicinal product is submitted simultaneously in several Member States, one of them being chosen as the “Reference Member State”. At the end of the procedure national marketing authorisations are granted in the reference and in the concerned Member States.
Purely national authorisations are still available for medicinal products to be marketed in one Member State only.
Special rules exist for the authorisation of medicinal products for paediatric use, orphan drugs, traditional herbal medicinal products, vaccines and clinical trials.

The EMA and the authorisation procedure

In 1993 the European Medicines Agency (EMA) was founded with the primary task of providing scientific advice of the highest possible quality to the Community Institutions on all matters relating to medicinal products for human and veterinary use. EMA’s main task is to co-ordinate the scientific evaluation of the safety, efficacy and quality of medicinal products which undergo either procedure. All scientific questions arising in these procedures are dealt with by the EMA.
The agency has today established itself as a world-leading agency for the evaluation of medicinal products. It constitutes a major asset in making Europe an attractive location for new pharmaceuticals and allows for speedy and robust authorisation of new innovative medicines.
EMA’s key tasks are to:
  • provide Member States and Community institutions with the best possible scientific advice on questions about the quality, safety and efficacy of medicinal products for human and veterinary use;
  • establish a pool of multinational scientific expertise (by mobilising existing national resources) in order to achieve a single evaluation via the centralised or mutual recognition marketing authorisation procedures;
  • organise speedy, transparent and efficient procedures for the authorisation, surveillance and where appropriate, withdrawal of medicinal products in the EU;
  • advise companies on the conduct of pharmaceutical research;
  • reinforce the supervision of existing medicinal products (by co-ordinating national pharmacovigilance and inspection activities);
  • create databases and electronic communication facilities as necessary to promote the rational use of medicines.

What is a Marketing Authorisation needed for?


Orphan Medicinal Product Designation in the EU

What is an Orphan Medicinal Product?



Data exclusivity for medicinal products in Europe…8+2+1 approach


Data exclusivity for medicinal products in Europe

The pharmaceutical sector is heavily regulated, with significant costs associated with both developing a new medicinal product and generating the data required to get a product to market. Protecting that data is therefore important.  Data exclusivity is a form of product exclusivity right for medicinal products in Europe, and market exclusivity is a related form of additional protection.
These two rights are in addition to any granted patent exclusivity right covering a medicinal product.

Why is data exclusivity granted?

The rationale for granting data and market exclusivity is to compensate the innovator company for the investment it has put in to developing the new medicinal product and to generating the data required to obtain a marketing authorisation.
Regulatory approval for medicinal products requires applicants to provide information about the efficacy and safety of their product to regulatory authorities. The first applicant for approval of a new medicinal product must provide a substantial body of data relating to the product (including the results of pre-clinical tests and clinical trials).
The regulatory regime permits generic companies, who subsequently wish to gain their own approval for the same drug substance, to rely on information filed by the innovator company that made the first application.  In order to be able to benefit from the data provided by the innovator in their regulatory filings for that medicinal product – the “reference medicinal product” – a generic company must show that their product has the same qualitative and quantitative composition as that product and that it is bioequivalent.

So what is the impact of a product enjoying “data exclusivity”?

An innovator company enjoys a period of “data exclusivity” during which their pre-clinical and clinical trials data may not be referenced in the regulatory filings of another company(typically a generic company) for the same drug substance.
For marketing authorisation applications made from November 2005 onwards, the period of data exclusivity in Europe has been harmonised as 8 years from the date of first authorisation in Europe.  For marketing authorisation applications made before November 2005, the period of data exclusivity varies from EU member state to EU member state, and is either 6 years or 10 years.
For marketing authorisation applications made from November 2005 onwards, there is an additional period of 2 years of “market exclusivity“.  This is the period of time during which a generic company may not market an equivalent generic version of the originator’s pharmaceutical product (although their application for authorisation may be processed during this period, such that they are in a position to market their product on the expiry of this additional 2 year period).

An extra year of protection for new indications

As noted above, the rules determining exclusivity changed in 2005. Under the “old rules” data exclusivity lasted either 6 or 10 years. The “new rules” follow an “8 + 2 + 1” year approach:
“Under the ‘old rules’ data exclusivity lasted up to 10 years. The ‘new rules’ follow an ‘8 + 2 + 1’ year approach.”
  • During the first 8 years from the grant of the innovator company’s marketing authorisation, data exclusivity applies.
  • After the 8 years have expired a generic company can make use of the pre-clinical and clinical trial data of the originator in their regulatory applications, but still cannot market their product.
  • After a period of 10 years from the grant of the innovator company’s marketing authorisation, the generic company can also market their product, unless the innovator product qualifies for a further one year of exclusivity.
  • This additional 1 year may be obtained in a number of circumstances, such as where the innovator company is granted a marketing authorisation for a significant new indication for the relevant medicinal product. In such a situation the generic company can only market their product after 11 years from the grant of the innovator company’s marketing authorisation.
How to Calculate Data Exclusivity Periods in Europe
An application for approval of a New Chemical Entity must contain data to allow assessment of the safety and efficacy profile. These data include pharmacological and toxicological tests and the results of clinical trials.
To avoid repeating such tests and trials, applications for generic pharmaceutical substances are not required to include these data; instead they may rely on the data provided in relation to the NCE application. However, EC directive 2001/83/EC prevents regulatory authorities from accepting applications for approval of generics that rely on this data until a data exclusivity period has expired.
This period starts on the day of the first marketing authorisation in the European Community (including Liechtenstein/Switzerland), and expires either six or ten years thereafter, depending on the country in which the application is to be filed and the procedure used to file it.
Data exclusivity relates to the active ingredient per se, new periods of data exclusivity are not applied to later approval of new dosage forms, routes of administration or indications. 1) To calculate the expiry of the data exclusivity period for centralised applications add 10 years to the corresponding European First Marketing Authorisation Date shown in the Pipeline Selector Report. 2) To calculate the expiry of the data exclusivity period for national or mutual recognition procedure applications, add the term from the following table to the corresponding European First Marketing Authorisation
Exclusivity …….Period ………..Country
10 Years
Belgium (BE) France (FR) Germany (DE) Italy (IT) Luxembourg (LU) Netherlands (NL) Sweden (SE) United Kingdom (UK)
6 years
Austria (AT) Denmark (DK) Finland (FI) Greece (GR) Iceland (IS) Ireland (IRL) Norway (NO) Portugal (PT) Spain (ES) Other, acceding countries*
* Poland has a data exclusivity period of 3 years for approvals prior to 1/5/2004 and 6 years thereafter. Hungary, Slovenia, Slovakia and Malta have requested transitional data exclusivity periods.
New Data Exclusivity Provisions for Europe A New Data protection directive (2004/27/EC) has been introduced in Europe, which provides eight years of protection from the first European Community marketing authorisation date, after which a European regulatory body may accept an application for approval of a generic. However, the product may not be marketed within ten years of the first European Community marketing authorisation date. An additional one year period of data exclusivity is allowed in respect of new indications with ‘significant clinical benefit’ over the existing indications. Approvals for other product line extensions, including different pharmaceutical forms, are regarded as a bundle of approvals for which only one data exclusivity period is available. This new directive applies only to data relating to NCE products submitted for approval after 31 October 2005, hence do not affect any of the current Pipeline Patent Intelligence products.

Generic applications in the EU, patents and exclusivity

Types of protection on the originator molecule that have to be taken into account by generic drug manufacturers when filing applications for generic drugs in the EU include the following:
  • patents at the time of marketing
  • supplementary protection certificates at the time of marketing
  • data/regulatory exclusivity at the time of regulatory submission
  • market exclusivity at the time of marketing.
Patents in the EU last for 20 years. Pharmaceutical products are normally covered by a number of patents, sometimes by as many as 30 to 40 patents or more. For pharmaceuticals these patents can be extended with a maximum of five years via a supplementary protection certificate.
A patent on a new use or ‘indication’, formulation, salt or ester can block the registration or marketing of a generic medicine for treatments where the original patent has already expired. This strategy is known as ‘evergreening’ aims to prevent or delay competition from generic medicines by extending market protection through patents on minor changes to the original product.
Data exclusivity
Data exclusivity is a separate and additional provision to patent protection for the originator medicine. With data exclusivity, there can be neither disclosure of regulatory data to a competitor nor regulatory reliance upon the data. Data exclusivity is the period during which no generic drug application can take place.
Therefore, generic medicines can only be evaluated and approved by the medicines regulatory authorities after the data exclusivity period has expired.
In the EU there is now an 8+2(+1) formula for data and marketing exclusivity, which means that originator’s data is protected for 8 years and they have marketing exclusivity for a maximum of 11 years from first marketing approval in the EU.
Exclusivity period: 8+2(+1)
The 8+2(+1) exclusivity period came into effect in the EU in late 2005.
8 years data exclusivity dating from the European Commission authorisation decision: before that, no generic applications may be filed.
+2 years marketing protection: no generic applications may be approved.
+1 year: new indication(s) if it constitutes a significant clinical benefit.
It applies for all products, regardless of whether they followed a centralised or national approval procedure.
It is not retroactive; it does not affect exclusivity periods for products for which applications were submitted before the effective date—late 2005.
Market exclusivity
With marketing exclusivity, the agency cannot allow a competing product to enter the market during the time period in which an innovator has a right of exclusivity.
Submission of generic applications is only possible after the expiry of the data exclusivity at year 8. However, there is no linkage of patent protection with registration. Approval of the application and launch of the generic can then take place at year 10 if there is no patent protection, and if there is no additional 1 year of marketing exclusivity due to a significant new indication registered for the reference product during the first 8 years of license, see figure below.