New FDA Draft Guidance ‘Data Integrity and Compliance with cGMP’ published

In the last years, the topic “data integrity” has become a priority for the FDA. Recently, the Agency has published the draft of a Guidance for Industry on the topic which presents the comprehensive opinion of the FDA on data integrity. Read more about the draft of the Guidance for Industry “Data Integrity and Compliance with cGMP”.–Data-Integrity-and-Compliance-with-cGMP–published_15555,15527,15062,15064,Z-COVM_n.html

In recent years, the topic “data integrity” has become a priority for European and American inspectors. At the beginning of 2015, the British authority MHRA published a first paper on that topic. Also in 2015, the World Health Organisation WHO issued another significant draft document on data integrity. Recently, the US American FDA has released the draft of a Guidance for Industry entitled “Data Integrity and Compliance with cGMP”. Although the FDA describes the Guidance as a non-binding recommendation, one may assume that the document presents the current thinking of the FDA regarding the topic.

The FDA criticises the fact that more and more cGMP deficiencies with regard to data integrity have been observed during inspections. Those deficiencies have led to a number of follow-up measures like Warning Letters or import alerts.

For the FDA, the integrity of data is one of the main quality issues. In the Guidance, the corresponding reference points in parts 21 CFR 211 and 21 CFR 212 are listed in detail as well as the principles for electronic records laid down in 21 CFR Part 11.

  • § 211.68 (requiring that “backup data are exact and complete,” and “secure from 48 alteration, inadvertent erasures, or loss”)
  • § 212.110(b) (requiring that data be “stored to prevent deterioration or loss”)
  • §§ 211.100 and 211.160 (requiring that certain activities be “documented at the time 51 of performance” and that laboratory controls be “scientifically sound”)
  • § 211.180 (requiring that records be retained as “original records,” “true copies,” or 53 other “accurate reproductions of the original records”)
  • §§ 211.188, 211.194, and 212.60(g) (requiring “complete information,” “complete 55 data derived from all tests,” “complete record of all data,” and “complete records of 56 all tests performed”).

The most important topics for the FDA are presented in the quite rare but not unusual form of questions and answers. The document contains 18 questions with their respective answers.

1. Clarification of terms
– What is “data integrity”?
– What is “metadata”?
– What is an “audit trail”?
– How does FDA use the terms “static” and “dynamic” as they relate to record formats?
– How does FDA use the term “backup” in § 211.68(b)?
– What are the “systems” in “computer or related systems” in § 211.68?
2. When is it permissible to exclude CGMP data from decision making?
3. Does each workflow on our computer system need to be validated?
4. How should access to CGMP computer systems be restricted?
5. Why is FDA concerned with the use of shared login accounts for computer systems?
6. How should blank forms be controlled?
7. How often should audit trails be reviewed?
8. Who should review audit trails?
9. Can electronic copies be used as accurate reproductions of paper or electronic records?
10. Is it acceptable to retain paper printouts or static records instead of original electronic records from stand-alone computerized laboratory instruments, such as an FT-IR instrument?
11. Can electronic signatures be used instead of handwritten signatures for master production and control records?
12. When does electronic data become a CGMP record?
13. Why has the FDA cited use of actual samples during “system suitability” or test, prep, or equilibration runs in warning letters?
14. Is it acceptable to only save the final results from reprocessed laboratory chromatography?
15. Can an internal tip regarding a quality issue, such as potential data falsification, be handled informally outside of the documented CGMP quality system?
16. Should personnel be trained in detecting data integrity issues as part of a routine CGMP training program?
17. Is the FDA investigator allowed to look at my electronic records?
18. How does FDA recommend data integrity problems identified during inspections, in warning letters, or in other regulatory actions be addressed?

Source: FDA Draft Guidance for Industry “Data Integrity and Compliance with cGMP”

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Five new General Chapters in the European Pharmacopoeia on Genotoxic Impurities in Pharmaceutical APIs

During the manufacture of APIs as sulfonate salts, esters of sulfonic acid may develop in undesired chemical side reactions. Recently, five new General Monographs have been included in the European Pharmacopoeia which describe how to cope with these impurities. Read more about these genotoxic impurities and the possibility to control them thanks to risk assessments.,S-AYL_n.html

Sulfonic acids are often used for the manufacture of pharmaceutical APIs. They serve as counterions in crystallisation processes, as protective groups or acid catalysts in API syntheses. Here, if short-chain alcohols such as methanol, ethanol or isopropanol are present, the formation of esters of these sulfonic acids can occur, which may have a genotoxic potential (alkylation of DNA).

The Mesilate Working Party which has been appointed in 2008 by the European Pharmacopoeia Commission has elaborated five General Chapters on different sulfonates which have been published in the European Pharmacopoeia Supplement 8.7 that came into force on 1 April 2016. The General Chapters are as follows:

  • 2.5.37 Methyl, ethyl and isopropyl methanesulfonate in methanesulfonic acid
  • 2.5.38 Methyl, ethyl and isopropyl methanesulfonate in active substances
  • 2.5.39 Methanesulfonyl chloride in methanesulfonic acid
  • 2.5.40 Methyl, ethyl and isopropyl toluenesulfonate in active substances
  • 2.5.41 Methyl, ethyl and isopropyl benzenesulfonate in active substances

As reported in a press release from the EDQM dated 25 February 2016 the completion of Chapter 2.5.41 marks the end of the Mesilate Working Party, as decided by the Ph. Eur. Commission. Simultaneously, the Commission had also decided to revise  the section “Production” in APIs-Sulfonates monographs and replace it by an additional standard text according to which the principles of risk management have to be used in the manufacture of APIs with regard to the genotoxic impurities. The text is as follows:

“It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers.”

Basically, the General Chapters of the European Pharmacopoeia will only be binding when they are referred to in a monograph; the only exception is when the reference made has only a recommendation character. This applies to all these five General Chapters. The purpose of the new text segment in the “Production” sections is to alert the applicant of a marketing authorisation of the risk related to such sulfonates impurities. He / she is not obliged to perform the analytical testing described in the general monographs; it is rather sufficient  to strongly justify the absence of these impurities by means of a risk assessment in the application. The ultimate decision whether this justification is suffiicient lies with the assessor of the competent authority.

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FDA releases draft guidance on the use of comparability protocols for post approval changes

The US FDA released a draft guidance for industry “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information”. The guidance replaces the draft guidance published in February 2003. It provides recommendations on implementing postapproval changes through the use of comparability protocols (CPs). Read more about FDA´s draft guidance for industry “Comparability Protocols for Human Drugs and Biologics”.

On April 19, 2016, the US Food & Drug Administration (FDA) released a draft guidance for industry “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information”. Comments and suggestions regarding the draft guideline should be submitted within 60 days of publication.

The guidance replaces the draft guidance published in February 2003. It provides recommendations on implementing postapproval changes through the use of comparability protocols (CPs). A CP is a comprehensive, prospectively written plan for assessing the effect of proposed CMC postapproval changes on the identity, strength, quality, purity, and potency of a drug product or a biological product. Using a CP in an original application or prior approval supplement (PAS) will, in many cases, facilitate the subsequent implementation and reporting of CMC changes. This could result in moving a product into distribution or facilitating a proactive approach to reinforcing the drug supply chain sooner than without a submitted protocol.

The guidance emphasizes that it is intended to establish a framework to promote continuous improvement in the manufacturing of quality products by encouriging applicants to employ tools of  ICH Q8 to Q11:

  • Effective use of knowledge and understanding of the product and manufacturing process;
  • A robust control strategy;
  • Risk management activities over a product´s life cycle;
  • An effective pharmaceutical quality system.

An FDA approved submission containing a CP provides an applicant with an agreed-upon plan to implement the proposed change(s), and in many cases, justification to report the implementation of the proposed change(s) in a reduced reporting category.

FDAs recommendations for the CP content: The CP submission should provide a comprehensive, detailed plan for the implementation of proposed changes and should include the information described below:

  • Summary;
  • Description of and Rationale for the Proposed Changes;
  • Supporting Information and Analysis (based on knowledge and risk assessments, information from development);
  • Comparability Protocol for the Proposed Change(s) – the CP should describe the specific tests and studies to be performed, including analytical procedures to be used and criteria to be achieved for the expected results. The level of detail that should be provided will depend on the complexity of the change and the specific risks associated with the change to product quality;
  • Proposed Reduced reporting category (i.e., an annual report, CBE, or CBE-30);
  • Other Information.

Additionally, the draft guidance provides a “Questions and Answers” section on CPs in the Appendix, which covers general questions and questions regarding formulation, manufacturing site and process, specification (including analytical methods), packaging, and process analytical technology (PAT) changes.

CPs together with “established conditions” may be effective tools for the overall product life cycle management. They can also facilitate the management of post-approval CMC changes in a more predictable and efficient manner, as it is the intention of the planned ICH Q12 Guideline “Lifecycle Management”. Steps 1 and 2 a/b of ICH Q12 are expected for June 2017.

For more information please visit the ICH website and see the FDA draft guidance for industry “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information“.

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GMP/GDP: When will I be inspected by the Authorities?

Various competent authorities are performing inspections. But who is subject to such an inspection?,15356,15274,15432,Z-QAMPP_n.html

GMP Inspections are carried out at Manufacturer Licence Holders

A manufacturer of medicinal products must meet Good Manufacturing Practice (GMP) standards. These standards are defined in various laws and regulations. In the EU the compliance with these regulations is checked and assessed by the national competent authorities. The overall goal is to have medicinal products of consistent high quality that meet the requirements of the marketing authorisation (MA) or product specification.

If a company supplies product to the USA, the U.S. Food and Drug Administration (FDA) might inspect the site assuring that drugs, medical devices, certain active pharmaceutical ingredients (APIs) and biological products manufactured in foreign countries and intended for U.S. distribution are in compliance with the applicable U.S. law and regulations.

GDP Inspections are carried out at Wholesale Dealer Licence Holders

Good Distribution Practice (GDP) requires that medicines are obtained from the licensed supply chain and are consistently stored, transported and handled under suitable conditions, as required by the MA or product specification. Many of the actors in the supply chain must implement GDP but are not under supervision. The competent authority for GDP will normally not carry out GDP inspections at transport companies (shipping companies) or at airport hubs.

You will also be inspected when you apply for a manufacturer or wholesaler dealer licence and then periodically, normally based on risk assessments. Overseas manufacturing sites are also inspected when medicinal products or certain APIs are imported to the EU.

Types of inspection

Inspections under a risk-based compliance programme

It is the aim of the competent authorities and inspectorates to prioritise regular inspections based on risk assessments. These inspections are generally announced in advance.

GMP inspections may sometimes be carried out with other inspections, such as with GDP, Good Clinical Practice (GCP) or Good Pharmacovigilance Practice (GPvP).

Product-related GMP inspections

Inspectorates may conduct product-related GMP inspections when assessing an application for a marketing authorisation. This inspection checks if the manufacturer complies with GMP. FDA may also carry out these pre-approval inspections. These inspections are generally announced in advance.

Product-related inspections can also be requested by the European Medicines Agency (EMA) for example by the Committee for Human Medicinal products (CHMp) during the pre-application of a centralised marketing authorisation application or the Co-ordination group for Mutual Recognition and Decentralised Procedures – human (CMDh). EMA uses inspectors from EU member states to ensure compliance with GMP principles.

Triggered or For Cause Inspections

Competent Authorities may inspect you if they are informed about possible GMP or GDP breaches for example by a whistle blower, the press/ media or another regulatory authority.

Here, only little or no notification of these inspections is given in advance.

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GMP Oversight of Medicines Manufacturers in the European Union

A System of Equivalent Member States, a Coordinating Agency and a Centralized Institution

The regulatory system for supervision of pharmaceutical manufacturers and GMP inspection in the European Union is one of the most advanced in the world. Due to the globalization of pharmaceutical manufacture, it also affects industry, regulators and patients outside the European Union. This system, however, is often poorly understood beyond the EU borders.

What follows is an explanation of the EU system in order to increase awareness and facilitate cooperation on GMP between European Union regulators and those outside the European Union.

The European Union

The European Union includes 28 Member States located in Europe, which are: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxemburg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and United Kingdom. The EU total population is about 500 million people.

The European Union operates through a system of supranational independent institutions and intergovernmental negotiated decisions by its Member States. It is a legal entity and can negotiate international agreements on behalf of its Member States. The European Parliament, the Council of the European Union and the European Commission are the three main EU institutions. They produce through the “Ordinary Legislative Procedure” (formerly “co-decision”) the policies and laws that apply throughout the European Union.

The European Union has developed a single market through a standardized system of laws that apply in all its Member States. The same rules and harmonized procedures apply to all the 28 Member States regarding the authorization of medicines and the supervision of safety of medicines.

The EU Regulatory System for Medicines

The EU has developed a regulatory system based on a network of decentralized National Competent Authorities (NCAs) in the Member States, supported and coordinated by a centralized agency, theEuropean Medicines Agency (EMA).

The European Commission’s role is multifaceted and focuses on the following:

  • Right of initiative: To propose new or amending legislation for the pharmaceutical sector
  • Implementation: To adopt implementing measures as well as to ensure and monitor the correct application of EU law
  • Risk management: To grant EU-wide marketing authorizations for centralized products or maximum residue limits on the basis of a scientific opinion of the EMA
  • Supervisory authority: To oversee the activities of the EMA in compliance with the mandate of the EMA, EU law and the EU policy objectives
  • Global outreach: To ensure appropriate collaboration with relevant international partners and to promote the EU system globally

The EMA was created in 1995 to coordinate the existing scientific resources in the EU Member States and is an interface for cooperation and coordination of Member States’ activities with respect to medicinal products. EMA scientific decisions are made through its scientific committees, whose members are chosen on the bases of their scientific expertise and are appointed by the Member States. One of the main roles of EMA is to mobilize scientific resources in the Member States, so that many of its scientific activities are carried out through a large network of scientific experts made available by the Member States.

The system for Marketing Authorisation (MA) of medicines, including the referral procedure, is an example of how the European Commission, the EMA and the Member States cooperate. The EU national, decentralized and mutual recognition MA procedures coexist with the centralized procedure (Table 1).

Table 1 - EMA GMP

The referral procedure is an EU binding mechanism that ensures that the same measures are applied to products subject to national, decentralized and mutual recognition MA procedures. This procedure may be notably invoked when the conditions of authorizations need to be reviewed in the light of quality, safety and efficacy data (Union Interest Referral), when Member States have adopted different decisions regarding products that are authorized in at least two Member States (Divergent Decision Referral) or in the absence of agreement among Member States in the course of the mutual recognition or decentralized authorization procedures (Mutual Recognition and Decentralised Referral). This mechanism involves an opinion from the appropriate EMA committee and results in a decision of the European Commission that is binding for all Member States.

In order to provide for the same level of access to critical medicines to all the patients in the Union, the centralized procedure is mandatory for orphan products, biotechnological products, advanced-therapy products (gene therapy, somatic cell therapy and tissue engineering) and products intended for the treatment of critical therapeutic classes (HIV or AIDS, cancer, diabetes neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases). Veterinary medicines for use as growth or yield enhancers are also in the mandatory scope of the centralized procedure.

A fundamental aspect is that the legislation applicable to pharmaceuticals in the European Union is the same irrespective of the Member State or authorization route of the product, as it is developed at Union level. The same applies to the guidelines in use by assessors and inspectors for the assessment of MA applications and inspections, which are developed by EMA, in cooperation with Member States, through its scientific committees and working groups.

Clinical trials of Investigational Medicinal Products (IMPs) require authorization by each NCA and a favorable opinion by an ethics committee in which the clinical trial takes place and is granted in the form of a Clinical Trial Authorisation (CTA). The assessment for a CTA takes into account the holding of an appropriate authorization for each EU site of manufacture or importation.

The EU System for GMP Supervision of Manufacturers and Inspection

Any manufacturer, no matter where it is located, must comply with GMP if they are to supply products to the EU. There is a single system for GMP supervision of manufacturers which is valid throughout all the EU Member States; this includes authorized medicinal products for human or veterinary use placed on the market and IMPs used in clinical trials. The system is based on two main pillars, the authorization/registration of operators in the supply chain and inspection of those operators to ensure compliance with legal requirements, including compliance with GMP and the requirements in the MA or CTA.

Manufacturers and Importers of Medicinal Products*

Manufacturers and importers of medicinal products located in the EU need to be authorized to carry out their activities. This obligation also applies to manufacturers and importers of products only intended for export and IMPs. The competent authorities of each Member State are responsible for granting the authorizations for these activities occurring within their respective territory.

A condition for grant of a manufacturing or import authorization is that the manufacturers must comply with EU GMP. GMP principles and guidelines are set out in two Directives, one for medicines for human use and the other for medicines for veterinary use. More detailed guidelines have been developed through the work of the GMP and GDP Inspectors Working Group (GMDP IWG) and the European Commission and included in the EU GMP guide, published on the European Commission website.

Inspection of Manufacturers and Importers of Medicinal Products

Manufacturers and importers of medicinal products located in the European Union or manufacturers located in a third country are regularly inspected by an EU competent authority for compliance with EU GMP. The outcome of these inspections must be accepted by all other EU authorities. After every inspection a GMP certificate (positive outcome) or noncompliance report (negative outcome) must be issued by the inspecting authority and entered in the EudraGMDP database, which is accessible by regulators in other countries. Most of this information is also available to the general public.

Inspections of manufacturers are typically requested in order to grant or maintain a manufacturing or import authorization (EU sites) or in the context of assessment, approval and maintenance of an MA (typically sites outside the EU) or CTA. For example, EMA may request that an EU competent authority undertake a preapproval GMP inspection of a site included in a MA application through the Centralised procedure or that an EU competent authority undertake periodic repeated postauthorization surveillance inspections of sites named in centralized MAs, in order to verify ongoing compliance with GMP and that the requirements of the MA are being met.

According to EU legislation, the interval for repeated GMP inspection should be based on risk. As a result, a procedure outlining a risk-based model to frequency of inspections is included in theCompilation of European Union Procedures on Inspections and Exchange of Information.

Manufacturers and Importers of Active Substance**

Manufacturers, importers and distributors of active substance located in the European Union are required to comply with GMP and must be registered to the National Competent Authority of the Member State where they are located.

For active substances manufactured outside the EU and imported, each batch needs to be accompanied by a written confirmation issued by the competent authority of the country where it is produced, confirming, among other things, that GMP at least equivalent to that in place in the European Union has been applied to its manufacture. The competent authority of the exporting country also needs to confirm that any GMP noncompliance arising at the manufacturing site would be communicated to the European Union. The receipt of this noncompliance information is via the EMA.

The requirement for the written confirmation can only be waived if the third country is included by the European Commission, after assessment, in a list of countries with an equivalent system of supervision and inspection or, exceptionally, in order to ensure availability of medicines in the EU market, if a GMP certificate for the site has been issued by an EU competent authority after inspection.

The requirement for written confirmation, introduced from July 2013 by Directive 2011/62/EU (the so called Falsified Medicines Directive), requires that authorities outside of the EU take responsibility for active substances manufactured in their territory, if exported to the EU. This requirement caused some debate before its implementation since there were concerns on its potential to cause shortages in the EU, if the exporting authorities were not willing or able to provide the written confirmations, which turned out not to be the case.

The increased dialogue and mutual understanding between the EU and the authorities of exporting countries was instrumental to ensure a smooth implementation of this requirement. It is a good example of the importance of regulatory cooperation in the current globalized manufacturing and supply environment to the benefit of all.

Inspection of Active Substance Manufacturers

The EU legislation places the responsibility for using active substances manufactured in compliance with GMP on the medicinal product manufacturer or the importer (in case the medicinal product is manufactured outside the European Union). The holder of the manufacturing authorization (medicinal product manufacturer in the European Union or EU importer) must verify the registration status of the manufacturer of the active substance and verify compliance by the manufacturer of active substance with GMP, by conducting audits at the manufacturing site. The holder of the manufacturing authorization shall verify compliance directly or they may use a third party acting under a contract.

Inspections of active substance manufacturers are carried out by EU competent authorities following a risk-based approach, or if there is suspicion of noncompliance.

Furthermore, every application for an MA must include a confirmation that the holder of the manufacturing authorization has verified compliance of the manufacturer of the active substance with principles and guidelines of GMP. The confirmation shall contain a reference to the date of the audit and a declaration by the Qualified Person that the outcome of the audit confirms that the manufacturing complies with GMP principles and guidelines.

Inspections of active substance manufacturers may also be organised by the European Directorate for the Quality of Medicines & Healthcare (EDQM) of the Council of Europe, on behalf of the EU. The Council of Europe has 47 members including all EU Member States and it has close cooperation with the EU. EDQM is responsible for developing and maintaining the European Pharmacopoeia.

EDQM issues Certificates of Suitability with the monographs of the European Pharmacopoeia (CEP) that can replace most of the data normally expected in EU MA dossiers for the active substance. In order to issue and maintain these certificates, EDQM runs its own inspection program of active substance manufacturers. Most of the inspections organised by the EDQM are carried out by inspectors from EU inspectorates.

The Supervisory Authority

As inspections are carried out by inspectorates of Member States, in order to avoid duplication it is necessary to identify the Member State responsible for supervision and inspection of any manufacturing sites involved in production of active substances and medicines for the EU market. This is achieved through the identification of one or more Supervisory Authority (SA); the SA is the NCA in the EU responsible for the GMP supervision of the site, including granting the manufacturing or import authorization and GMP inspection.

If the manufacturing site is in the EU, the SA is the NCA of the Member State where the site is located. In cases where the manufacturing site is outside the EU, the SA is the NCA of the Member State in which the importer of the product(s) is located. Where products from a manufacturing site located in a country outside the EU are imported in more than one Member State, there may be more than one SA, which cooperate in the supervision of the manufacturing site.

The Qualified Person & Batch Certification Prior to Release

An important feature of the supervision system in place in Europe is the role of Qualified Person (QP). In order to obtain an authorization, EU manufacturers and importers must have at their disposal the services of at least one Qualified Person. The Qualified Person must take responsibility for securing that each batch of medicinal product, manufactured or imported, has been manufactured in accordance with EU GMP, and must certify compliance with GMP and with the relevant MA(s). A batch may only be released by a manufacturer or importer for distribution in the EU after certification by the QP. Member States are empowered to take administrative and disciplinary measures against QPs if they have failed to fulfil their obligations.

Furthermore, imported batches need to undergo a full retest in the EU to ensure the quality of the product in accordance with the MA specification. There-testing requirement is waived if there is an operational Mutual Recognition Agreement in place between the EU and the exporting country.

Consequences of Noncompliance with EU GMP

The discovery of serious GMP noncompliance may have implications not only for the Member State which carries out the inspection but also other, possibly all, Member States as well as international authorities should the active substance or product be supplied to them. A mechanism that ensures a coordinated approach for protection of public and/or animal health is taken throughout the European Union has been developed and is published in the Compilation of European Union Procedures. The objective of this procedure is to achieve a coordinated and harmonized assessment and proportionate supervisory actions to balance the protection of patients and minimize supply disruptions whilst ensuring maximum efficiency and avoiding full parallel reviews on a national level across the European Union.

European legislation provides that manufacturer and import authorizations may be suspended or not granted as a result of noncompliance with GMP. Also, existing MAs for the products affected can be varied (e.g., to delete a certain manufacturing site), not granted or revoked. Urgent measures include prohibition of manufacture, importation or supply, and/or withdrawal of all, or of specific batches from the market.


EudraGMDP is a publicly accessible Union database which is a repository of, among other things, manufacturing and import authorizations, GMP certificates and non-compliance reports. After every GMP inspection carried out by an EU competent authority, a GMP certificate (positive outcome) or a noncompliance report (negative outcome) is issued by the inspecting authority and entered in the EudraGMDP database.

The database includes a planning module (only accessible to the relevant regulators) for coordination of inspections planned by EU authorities in countries outside the European Union. Data are entered into the planning module in order to facilitate exchange of information between competent authorities and reduce duplication and ensure the best use of inspectional resources. EMA and EU authorities recognize the global nature of modern pharmaceutical supply chains and the need for close collaboration and cooperation with regulatory authorities outside the European Union and therefore work is ongoing to extend the use of the EudraGMDP database planning module to include exchange of information on inspections planned by authorities outside the European Union.

Overview of Inspection Activities

The chart below shows a summary of the inspections carried out by EEA competent authorities in 2014. Domestic inspections are inspections carried out by EEA competent authorities within the EEA territory. Foreign inspections are inspections carried out by EEA competent authorities outside the EEA. The data are extracted from EudraGMDP.


Ensuring and Maintaining Equivalence among Member States Inspectorates

In order to ensure the functioning of the EU system for GMP supervision of manufacturers and inspections described above, it is necessary to ensure that all the National inspectorates in the Member States are equivalent as regards the level of supervision they are able to provide. A number of measures are put in place to ensure that this is the case, summarized below.


The pharmaceutical legislation is developed at EU level, mainly in the form of Regulations and Directives. Both are applicable to all the Member States, the difference being that Regulations are directly applicable to the entire EU territory while Directives have to be transposed into national legislation, in a timeframe established in the Directive itself, usually 18 months.

The EU legal framework for medicinal products is intended to ensure a high level of public health protection and to promote the functioning of the EU internal market. The system is also designed to encourage innovation. It is a large body of legislation that ensures extensive harmonization within the European Union, including GMP and inspections. The pharmaceutical legislation is published in the Official Journal of the European Union.

The EU GMP guide

A single GMP guide is in use in the European Union. The guide is referenced in the EU legislation (Directives 2001/83/EC for human products, 2001/82/EC for veterinary products and in clinical trial legislation) and has long since replaced any previously existing national GMP guide. The EU GMP guide provides the standards and requirements used by EU inspectors for any GMP inspections, both in or outside of the European Union.

The guide is subdivided into tree parts and 19 annexes dealing with specific types of manufacture. Part 1 is the GMP for finished products, Part 2 GMP for active substances and Part 3 includes GMP-related documents. The EU GMP guide is harmonized with the PIC/S GMP guidelines on an ongoing basis. EU GMP Part 2 reflects the EU’s agreement to the ICH Q7 guidelines and forms the basis of the detailed guidelines.

The Compilation of European Union Procedures on Inspections and Exchange of Information

The Compilation of European Union Procedures on Inspections and Exchange of Information (CoUPs) is a collection of procedures for GMP and Good Distribution Practice (GDP) inspectorates, applicable to all the inspectorates in the European Union. It provides a tool to facilitate cooperation between EU Member States and a means to achieve harmonization. The CoUP covers, among other things, the basis for national procedures that form part of the national inspectorates’ quality systems, how quality defects and noncompliance are handled and how GMP and GDP inspections are carried out and reported.

The contents of the CoUP are constantly updated, developed and agreed, under the coordination of the EMA, by representatives of the Inspectorates of each Member State, including those supervising the manufacture and import of veterinary medicinal products only. Once agreed, they are adopted by the European Commission and then published on its behalf by the EMA.

Common Union formats for manufacturing and import authorizations, GMP certificates and for statements of non-compliance with GMP have been agreed and published in the compilation and implemented by EU competent authorities in order to enhance communication, collaboration and co-operation between authorities. This common format enables Member States to enter manufacturing, importing and distribution authorizations in the Union database, EudraGMDP.

The GMP/GDP Inspectors Working Group

The GMP/GDP Inspectors Working Group (GMDP IWG) is a group of senior inspectors appointed by all the EEA competent authorities which meets at EMA premises four times a year. It is chaired by EMA and a European Commission representative attends the meetings, as well as observers from the European EDQM, accession countries (countries which have applied to be part of the EU but have not joined yet) and MRA partners. Representatives from other international authorities can be invited on a case-by-case basis.

The group is a forum for harmonization and discussion of common issues which are taken by the inspectors back to their NCA for implementation. Any new or amended text of the EU GMP guide is developed by this group, with the European Commission responsible for the final adoption. The GMDP IWG also maintains the CoUP and oversees, on behalf of the Heads of Medicines Agencies (HMAs) the Joint Audit Programme.


The GMDP IWG organises training for EEA inspectors and inspectors from accession countries, aimed at raising the technical capability of the inspectors, ensuring common understanding of issues related to GMP and harmonization. In addition, EMA has signed a partnership agreement with PIC/S on cooperation on training for GMP inspectors, which recognizes the role that PIC/S plays in this area and avoids duplication of effort.

Ensuring Equivalence before Joining the EU

Becoming a member of the European Union is a complex procedure and there are strict conditions for EU membership to ensure that new members are admitted only when they are fully able to take on the obligations of membership, including compliance with all the EU’s standards and rules. For the purpose of accession negotiations, these are divided into 35 different policy fields(chapters).

For acceding to the EU, a candidate country must implement the EU rules and regulations in all areas. The length of the membership negotiations can vary and depends on the time needed to complete the necessary reforms and the alignment with EU law. The candidates are supported financially, administratively and technically during this preaccession period.

In order to ensure that new Member States joining the European Union have reached the same level as the other members before the date of accession, a number of measures are put in place. These include:

  • The European Commission checks compliance with the EU legislation (including pharmaceutical legislation)
  • Through the TAIEX program, financed by the European Commission, technical support may be provided
  • Accession countries are invited as observers to EU meetings (including the GMDP IWG)
  • Specific training on EU procedures is organized

Auditing Member States

Auditing is an important part of the measures put in place in order to oversee the equivalence of Member States. There are a number of contexts in which Member States NCAs and/or inspectorates can be audited.

The Joint Audit Program (JAP) of the EU NCAs’ GMP inspectorates is an internal audit program under the Heads of Medicines Agencies (HMA) and is run on behalf of HMA by the GMDP IWG. JAP aims at achieving and maintaining equivalence between Member States’ national inspectorates responsible for GMP. It was established in October 2000 and is an important part of the quality system adopted by all GMP inspectorates in the EU.

JAP auditors are senior GMP inspectors, further qualified for auditing inspectorates through specific training. A list of qualified JAP auditors is maintained by the Compliance Group, which is a subgroup of the GMDP IWG. JAP auditors also provide technical advice and support to accession countries before they become EU Member States.

EU inspectorates are audited through the JAP onsite, at intervals established through a risk-based approach (typically every five to six years). Mutual Recognition Agreement and other international partners are invited on a case-by-case basis to join JAP audits of EU Member States inspectorates as observers.

Audits are also organized in the framework of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) and Mutual Recognition Agreement (MRA) (see International Cooperation Activities below). Since most of the EU authorities and all MRA partners are member of PIC/S, synergies between the various audit schemes are used in order to avoid duplication.

BEMA Audits

The Benchmarking of European Medicines Agencies (BEMA) is an internal EU program managed by the Heads of Medicines Agencies, based on assessment of the systems and processes in individual agencies against a set of indicators in four main areas:

  • Management systems
  • Assessment of marketing authorization applications
  • Pharmacovigilance (drug safety) activities
  • Inspection services

The assessment identifies strengths and best practices in agencies and any opportunity for improvement. The program has concluded its third cycle in 2015.

International Cooperation Activities

The European Union and its Member States are involved in several bilateral and multilateral cooperation activities with international partners in the GMP area. The main advantage is that international cooperation allows, by relying on information received from trusted international authorities, to reallocate foreign inspections towards areas more at risk. It thus optimizes available inspection resources.


The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) aims at harmonizing inspection procedures worldwide by developing common standards in the field of GMP and by providing training opportunities to inspectors. It also aims at facilitating cooperation and networking between competent authorities, regional and international organisations, thus increasing mutual confidence. Most EU Member States are members of PIC/S while EMA is participating in PIC/S activities as a partner organization.

Mutual Recognition Agreements

Mutual Recognition Agreements (MRAs) are official agreements on the mutual recognition of assessment of conformity of regulated products which are negotiated and signed at EU level. MRAs concluded by the European Union include pharmaceuticals and cover GMP. Consequently, inspection results carried out by MRA partners in their territory are recognized by EU Member States and vice versa and retesting upon importation into the European Union is not needed in the QP batch certification process. The MRA scope can cover both human and veterinary products, finished products, active substances and Investigational Medicinal Products, but there are differences in scope between the various MRAs.

Currently, the European Union has operational MRAs in place with Australia, Canada, Japan, New Zealand and Switzerland. The EU also has in place an Agreement on Conformity Assessment and Acceptance of industrial products (ACAA), which includes GMP, with Israel. An ACAA is a specific type of MRA; the main practical difference is that in the ACAA case results of inspections carried out outside the territory of the agreement partners are mutually recognized as well, in addition to inspections carried out in the partners’ territory. An MRA between the European Union and the United States was signed in 1999; at the time of this writing it is operational only toward rapid alerts.

International Coalition of Medicines Regulatory Authorities

The European Commission, EMA and some EU Member States (France, Germany, Ireland, Italy, Spain and UK) participate to the activities of the International Coalition of Medicines Regulatory Authorities (ICMRA). ICMRA is a recent initiative started by Heads of Medicines Agencies worldwide, which aims at providing global strategic coordination and direction on areas that are common to many regulatory authorities’ missions worldwide, and which builds on existing arrangements such as those of PIC/S. The ICMRA has the objective to establish synergies and to foster global cooperation among regulators and GMP is one of the ICMRA main areas of interest.

Other International Cooperation Activities

In addition to MRAs, the European Union is involved in several less formalized cooperation schemes on GMP with international partners and/or in areas not covered by an MRA.

The API international cooperation project has as main objectives the sharing of information on inspection planning, policy and inspection reports and joint inspections on manufacturers located outside the participating countries. It includes the following participants: the EMA and all EU member States, the European EDQM, the U.S. FDA, the Australian Therapeutic Goods Administration (TGA) and WHO.

Several bilateral pilots and programs between EMA and FDA were also developed during the last ten years with the view to increase collaboration on domestic and third country GMP inspections.

This less formal form of cooperation in the last years has allowed the building of confidence among cooperating countries and regions, mainly through joint inspections and exchange of information, and is opening new possibilities of mutual reliance on inspection results. In this perspective, it is worth noting that the European Union has identified the recognition of GMP inspections carried out in the European Union and the United States and in third countries as a main objective for the pharmaceutical sector in the context of the negotiations of the Transatlantic Trade and Investment Partnership (TTIP).

Disclaimer: The views expressed in this article are those of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the Agencies or Institutions with which the authors are affiliated.


*The term “Medicinal Product” in the European Union approximately corresponds to the term “Drug Product” in the United States. Sometimes the term “Finished Product” is used instead.

**The term “Active Substance” in the European Union corresponds to drug “Drug Substance” in the United States.

Tags: EMA , Europe , inspections , GMP , EC , European Commission , European regulations , PIC/S , GMP regulation

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

New Details on the Revision of USP Chapter 1



As already reported, Chapter <1> of the US American Pharmacopoeia has been revised again. Find out more about the chapter on Injections and Implanted Drug Products (Parenterals)-Product Quality Tests.,15266,Z-PEM_n.html

As already reported in the news “Second Revision of USP Chapter <1> Injections and Implanted Drug Products (Parenterals)-Product Quality Tests“, USP’s Chapter <1> “Injections and Implanted Drug Products (Parenterals)-Product Quality Tests’ has been revised again. New information is now available.

The USP published these details on 25 March. The revised version now contains a table of contents for a better overview whereas the Product Performance Test at the end of the Chapter has been deleted. All details about the new version of USP’s Chapter <1> can be found on the USP website.

The revised Chapter will become effective on May 1st, 2016.

//////////Revision,  USP Chapter 1, US American Pharmacopoeia

The new Annex 16 “Certification by a Qualified Person and Batch Release” will become effective as of 15 April 2016.

The new Annex 16 is coming into Force

The new Annex 16 “Certification by a Qualified Person and Batch Release” will become effective as of 15 April 2016. The contents will reflect the coming state of expectations regarding the batch release.


The new Annex 16 “Certification by a Qualified Person and Batch Release” will become effective as of 15 April 2016.

It is centrally pointed out that the main duty of a Qualified Person (QP) is the certification of batches. In this context, the QP must personally ensure that the responsibilities listed under Chapter 1.6 are fulfilled. Chapter 1.7 lists many other responsibilities to be guaranteed by the QP. However the related activities can be delegated and the QP can rely on the respective quality management systems. Yet, the “QP should have on-going assurance that this reliance is well founded” (1.7). The 21 responsibilites listed include amongst others:

  • The starting materials used comply with the requirements and the supply chain is known and under control.
  • The necessary audits have been carried out and the audit reports are available.
  • The manufacturing processes and testing methods are validated and in accordance with the marketing authorisation.
  • Changes have been assessed and completed accordingly.

In this context, it is important to mention that the Annex clearly highlights that the overall responsibility (safety, quality and efficacy) for a medicinal product lies with the marketing authorization holder (MAH). “However, the QP is responsible for ensuring that each individual batch has been manufactured and checked (…) in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP)” (see general principles).

In cases where the QP has to rely on the functioning QM system of another site, the QP must ensure that a documented review and permission of audit reports by third parties is available.

Another important section clarifies the role of the QP with regard to deviations and includes a few elements from EMA’s position paper on QP Discretion (published in February 2006 and updated in January 2008). Chapter 3 of the new Annex describes the “handling of unexpected deviations”. A batch with an unexpected deviation concerning the manufacturing process may be certified if the result of a risk analysis performed shows that “the potential impact of the deviation on quality, safety or efficacy of the batch(es) concerned and conclusion that the impact is negligible.” In cases where a deviation concerns specification defined in the marketing authorisation as essential for the release (OOS; out of specification), the QP will still have no scope left.

During the consultation phase, interest groups have expressed their concerns with regard to the sampling of imported products. Now, the new Annex 16 makes clear that “samples may either be taken after arrival in the EU, or be taken at the manufacturing site in the third in accordance with a technically justified approach which is documented within the company’s quality system. (…) Any samples taken outside the EU should be shipped under equivalent transport conditions as the batch that they represent.”

Regarding any requirements on import, the new Annex 16 “Certification by a Qualified Person and Batch Release” has been kept relatively short. Those requirements will probably be set in the new Annex 21.

//////new Annex 16,  Certification by a Qualified Person and Batch Release,  15 April 2016, Qualified Person (QP),  certification of batches

ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities

ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities

Two general monographs of the European Pharmacopoeia have been revised and published for comment in the newest “Pharmeuropa” edition. Read more about what you will have to consider in future with regard to the control of elemental impurities in pharmaceutical preparations, APIs and excipients.


In a press release dated 30 November 2015, the EDQM announced the revision of two general pharmacopoeial monographs: “Substances for pharmaceutical use” (2034) and “Pharmaceutical preparations” (2619). The decision was taken during the 153rd session of the European Pharmacopoeia Commission; the Commission follows its strategy for implementing the ICH Guideline Q3D “Guideline for Elemental Impurities” in the European Pharmacopoeia. A section “Elemental Impurities” has been added to both monographs which emphasizes that the provisions laid down in General Chapter 5.20 of the Pharmacopoeia (identical in wording with ICH Q3D) apply to the limits of metallic impurities and to their control. For pharmaceutical preparations and substances for pharmaceutical use outside the scope of Chapter 5.20 (e.g. unlicensed patient-specific preparations, herbal products, radiopharmaceuticals, etc.), the manufacturer is obliged to perform a risk assessment with regard to the limits of those impurities and – if necessary – to use validated analytical procedures for their determination. The principles to be applied for such a risk assessment arise from a press release from the EDQM dated 7 August 2015: it is expected that the provisions defined on the Guidelines ICH Q3D or ICH Q9 are followed. Lastly, according to this press release, the control strategy of elemental impurities as well as the substantial demonstration of suitability of the analytical methods used in the marketing authorisation dossier remains in the responsibility of the manufacturer.

The definition of “Substances for pharmaceutical use” in the monograph 2034 states: “Substances for pharmaceutical use are any organic or inorganic substances or excipients for the production of medicinal products for human or veterinary use. … Substances for pharmaceutical use may be used as such or as starting materials for subsequent formulation to prepare medicinal products. Depending on the formulation, certain substances may be used either as active substances or as excipients.”

The drafts of the two revised general monographs are accessible for free in the Journal “Pharmeuropa“, Edition 28/2. You only need to register and log in with your password. The comment deadline for both monograph drafts ends on 30 June 2016.





Other reading Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf October_21_2014.pdf October_21_2014.pdf

///////ICH Q3D,  implemented,  European Pharmacopoeia, Revision, Two General Monographs,  Elemental Impurities

QP Education and Qualification – What is needed?


We are frequently asked about the educational requirements in order to become a Qualified Person in Europe. Comprehensive educational modules are offered, especially in the UK. These training courses contain different topics like pharmaceutical law, Microbiology, Quality Management etc and require the trainee to take part in multiple courses over an extended period. But is this needed to become a QP in Europe?

Read more about QP education and qualification.



We are frequently asked about the educational requirements in order to become a Qualified Person in Europe. Comprehensive educational modules are offered, especially in the UK. These training courses contain different topics like pharmaceutical law, Microbiology, Quality Management etc and require the trainee to take part in multiple courses over an extended period. But is this needed to become a QP in Europe?

The answer comes in two parts.

First: If you are located in the UK then those training courses and modules might be useful in order to prepare for a QP exam (but they are not mandatory).

Second: In all other countries there is no need to go through all these modules. The European legislation does not contain any requirement for specific additional educational programmes.

In order to become a Qualified Person in Europe the requirements are laid down in the EU Directive 2001/83:

1) 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. Further special cases are explained in more detail in Article 48 of the EU Directive.
2) The qualified person shall have acquired practical experience over at least two years, in one or more undertakings which are authorized to manufacture medicinal products, in the activities of qualitative analysis of medicinal products, of quantitative analysis of active substances and of the testing and checking necessary to ensure the quality of medicinal products. The duration of practical experience may be reduced by one year where a university course lasts for at least five years and by a year and a half where the course lasts for at least six years.

Each EU Member State has implemented the above mentioned EU Directive into national law. There are slight differences in each EU Member State, but with the exception of the UK all other EU Member States do not require a defined exam by an official body in order to be named as a QP on the manufacturing license of a pharmaceutical company.

However, it is strongly recommended that Qualified Persons receive initial and ongoing education in Good Manufacturing Practice (GMP). The ECA Academy for example offers a wide range of GMP training courses which are helpful for QPs. But QPs and those who want to become a QP are free to select those topics which are of interest and are helpful to perform the daily work as a QP rather than a standardized scheme. This means that the recommended training course should be different for a QP working in aseptic manufacturing compared to a QP in solid dosage form manufacturing, herbal drug manufacturing or in biopharmaceutical manufacturing. There is no “one fits all approach”.

You may want to read the article The role of the Qualified Person in pharmaceutical legislation to learn more.


////////// Qualified Person in Europe, pharmaceutical law, Microbiology, Quality Management, QP education, qualification,

EDQM adopts revised monograph for WFI allowing non-destillation techniques


In a press release the EDQM has announced that the new monograph draft on Water for Injection (169) had been adopted. Read on to learn more about the production of WFI with membrane systems.,15160,15090,15267,Z-PEM_n.html


In a press release, the European Pharmacopeia Commission has announced that the revised monograph on Water for Injection (WFI) had been adopted.

According to the revised monograph, it will be allowed in Europe in future to produce WFI with a purification method equivalent to distillation like e.g. reverse osmosis coupled with appropriate techniques. Moreover, the EDQM declares that a notice to the respective supervisory authorities will be required when a “non-distillation” technology is used for the production of WFI. Besides, the EDQM points out that it is not only a matter of equivalence of a specification but rather the robustness of the purification of WFI. Therefore, Annex 1, which is currently under revision, will also include requirements with regard to the production of WFI. The new Annex 1 will be available when the revised monograph becomes applicable.

With the modification of this monograph, harmonisation with the US Pharmacopeia and the Japanese Pharmacopeia goes one step further. In both countries, non-distillation technologies for the production of WFI are already allowed.

The revised monograph Water for Injections (169) will be published in Ph.Eur. Supplement 9.1 and apply as of April 2017. For further information please see the EDQM’s press release.


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