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

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

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