Drug Master File Procedures in the EU, the US and Japan 22-23 October 2015, Hamburg, Germany

Drug Master File Procedures in the EU, the US and Japan

22-23 October 2015, Hamburg, Germany


Marieke van Dalen, Aspen Oss B.V, The Netherlands

Dr Hiltrud Horn, Horn Pharmaceutical Consulting, Germany

Dr Usfeya A Muazzam, Bonn, Germany
Dr Boris Pimentel, DSM-Nutritional Products AG, Switzerland
Dr Wilhelm Schlumbohm, Berlin, Germany



Learning Objectives

This education course is intended to provide guidance on the procedures for the European ASMF, the US-DMF and the Japanese DMF. You will get to know
how to describe manufacturing processes
how to compile data for drug substance stability, impurities and residual solvents
which are the important points to consider for US-DMFs
which are the requirements for Japanese DMFs
how to handle changes in European, US and Japanese DMFs

Participants will have the opportunity to take part in one of two parallel workshops about
Description of the manufacturing process or How to compile data for Impurities and Residual Solvents


Documentation of the drug substance quality is an integral part of any marketing authorisation application. In Europe the most common document for this purpose is the Active Substance Master File (ASMF) as long as the applicant has no Certificate of Suitability of the pharmacopoeial monograph (CEP). The European ASMF procedure differs significantly from the US-DMF procedure and for strategic reasons it is very important to take these differences into account. Moreover there are particular requirements for DMFs in Japan. For global acting companies it is a big challenge to handle the different procedures of compiling, submitting, changing and maintaining Drug Master Files in an efficient way.

Target Group

The education course is designed for all persons involved in the compilation of pharmaceutical dossiers for marketing authorisations especially for Drug Master Files who want to become familiar with the different DMF procedures. Furthermore, the course will be of interest to personnel from Quality Units of the pharmaceutical and the API industry.


The European Active Substance Master File procedure – An Introduction
Chemical pharmaceutical documentation for active substance(s) –
Regulatory requirements in EU, USA
Types of active substances – types of documentation
CTD Module 3, CEP and ASMF (former DMF)
CEP for a substance for TSE risk assessment

Drug Master File Procedures in the US
Types of Drug Master Files
Submissions to DMFs
Closure of a DMF
US vs EU DMF – differences in the procedure

How to document drug substance stability
Stability Guidelines
Stability Testing of new drug substances and drug products
Storage Conditions
Bracketing and Matrixing Designs
Stability data from new drug dosage forms
How to document evaluation of stability data
Optimising the submission

Residual solvents and Impurities: synthesis derived Impurities, Metals and genotoxic Impurities
Impact of the new guidelines ICH Q3D and ICH M7
Sources of Impurities
Setting and justification of specifications
Residual solvents, solvent classes
Content and scope of data – documentation requirements
Frequent mistakes

Handling Changes in European Drug Master Files
Why is there a need for changes
Types of changes
How to communicate with the customers and how to get feed back
Differences between ASMF and CEP
How to maintain an ASMF
Keeping track of the customers’ stand in relation to a specific change

Handling Changes in US Drug Master Files
Post approval activities
Reporting requirements to the FDA (CBE 0, CBE 30, Annual Report)
Post approval commitments and post approval reporting requirements
Risk evaluation and mitigation strategies (REMS)
Major re-organisation of a US-DMF
Holder obligations

Requirements of the Drug Master File Procedure in Japan
Regulatory procedures in Japan
points to consider when dealing with Japanese authorities
Regulatory documentation standards
Master File registration procedure
Master File review by Japanese authority

Changes and Maintenance of Japanese Drug Master Files
Change procedures and communication with the Japanese authority
Types of changes
Notification of changes

Non-ECA Members: EUR 1.790,–
ECA Members: EUR 1.590,–
EU GMP Inspectorates: EUR 895,–
APIC Members (does not include ECA membership): EUR 1.690,–
(All prices excl. VAT)
If you have any questions, please contact us:

Tel.: +49 (0)6221 / 84 44 0 E-Mail: info@concept-heidelberg.de




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).


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.

Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7


Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7

The APIC has thoroughly revised the “How to do” document that explains the guideline ICH Q7. Here you can see how the new document interprets the requirements concerning a GMP compliant manufacture of active pharmaceutical ingredients against the background of the current developments.


Shortly after the entry into force of the Good Manufacturing Guide for Active Pharmaceutical Ingredients ICH Q7 in the year 2000 the Active Pharmaceutical Ingredients Committee APIC wrote the “How to do” document which clarifies the requirements of the guideline on the basis of experience gained from operational practice. The present document aims at providing practical advice for the implementation and maintenance of GMP standards during the production of active pharmaceutical ingredients concerning those provisions of ICH Q7 that require further interpretation. The “How to do” document is a “living” document as it is revised in irregular intervals in order to keep pace with the constantly changing state of scientific and technical knowledge.

The recently revised version of the document was published as “Version 8” on the APIC publications website in August 2015. As compared to the last revision (August 2012) the chapters 10 “Storage and Distribution”, 11 “Laboratory Controls”, 12 “Validation” and 15 “Complaints and Recalls” were revised. The following is a selection of the most important changes:

Chapter 10 Storage and Distribution

  • This chapter points out the importance of controlling the temperature distribution in warehouses taking into account seasonal temperature changes. The document indicates sets of rules that describe concretely how to perform a temperature mapping (section 10.10.).
  • It stresses the necessity of physical separation between released and returned material, preferably by storing them in different rooms. Storage conditions for intermediates are based on development data and knowledge (section 10.11).
  • The document points out that logistics companies should be qualified (quality agreement). The shipping conditions records should be reviewed. If deviations occurred an investigation should be initiated and appropriate measures be carried out and documented (section 10.21).

Chapter 11 Laboratory Controls

  • This chapter expressly points out that analytical methods have to be validated and that the integrity of analytical data has to be ensured by means of controls (section 11.11).
  • Rounding rules and the process used for averaging should be described in a SOP (section 11.11.).
  • In chapter 11.13 ICH M7 and ICH Q3D have been added to the list of ICH guidelines. Furthermore, it is pointed out that the design of experiments approach can also be used within the framework of design space when defining specifications.
  • Chapter 11.15 contains detailed guidance on the FDA requirements for active pharmaceutical ingredients that are exported to the USA and sold there, especially on the handling of OOS results.

Chapter 12 Validation

  • Chapter 12.11 explains more in detail the handling of critical parameters and quality attributes referring to the actual ICH guidelines ICH Q8 and Q11 as well as to FDA and EMA guidelines.
  • It indicates that the 3 consecutive validation batches should be considered as an orientation. The actual number of validation batches has to be pre-defined and to be justified (section 12.50).
  • The process validation report has to contain all critical quality attributes compared to the reference batches. These attributes should be comparable to or better than the reference batches. The rationale for selecting the reference batches must be justified (section 12.52).

Chapter 15 Complaints and Recalls

  • This chapter refers to the necessity to include other batches potentially connected with the batch affected by the complaint or recall in the complaint investigation and to define a period to close complaint investigations (section 15.10).
  • It points out that a recall cannot be carried out by the API manufacturer himself. This is the responsibility of the finished dosage form manufacturer. The notification of the authorities (such as public health departments) can also only be carried out in close cooperation with the finished dosage form manufacturer (section 15.10).

As a whole the revised “How to do” document is a valuable aid for the implementation of the Good Manufacturing Practice in the production of active pharmaceutical ingredients. Due to the thorough revision of many sections it offers an up-to-date practice-oriented assistance every API manufacturing site can profit from


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.


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.

Sun, Wockhardt recall drugs from US market

Hyderabad: Sun Pharma and Wockhardt have separately initiated voluntary recall of a number of drugs from the US market due to different reasons.

Representational image. AFP

Sun Pharma initiated voluntary recall of multiple lots of Bupropion Hydrochloride Extended-¬release Tablets USP (SR), 200 mg, 60-count bottle, from the US market for “failed dissolution specification”, while Wockhardt started recalling its Lisinopril Tablets USP, 5 mg and 20 mg from the same market for “CGMP violations”.

According to a notification issued by the US Food and Drug Administration, Sun Pharma’s recall was initiated last month under Class-III classification which was as ‘a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences’

Sun, Wockhardt recall drugs from US market

read at……http://www.firstpost.com/business/sun-wockhardt-recall-drugs-from-us-market-2413690.html

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.



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.