EMA revises Guide on Pharmaceutical Water And open for Commnets

EMA revises Guide on Pharmaceutical Water

According to the European Pharmacopoeia, it will be allowed as of the 1st of April 2017 to produce water for injection (WFI) using cold i.e. non-distillation methods (as already reported under "WFI obtained by non-distillation methods - What are the Next Steps?"). Now, the European Medicines Agency (EMA) has published a concept paper on the revision of the Note for (Click Here for Download) Guidance on Quality of water for pharmaceutical use (CPMP/QWP/158/01 EMEA/CVMP/115/01). This Guideline from 2002 describes the different qualities of water for pharmaceutical use and their use in the production of medicinal products and/ or diverse dosage forms (e.g. topical, oral or parenteral). The paper also mentions the production of the different qualities and is in line with the present regulations of the European Pharmacopoeia which only allowed distillation for the production of WFI. The document also describes Highly Purified Water (HPW) and its use. HPW meets WFI quality but can be produced by means of membrane processes. Here, an essential aspect is the proposition of EMA's Quality Working Party  to remove in the future the monograph (1927) Highly Purified Water.

The (Click here) "Concept paper on the need for revision of note for guidance on quality of water for pharmaceutical use (H+V)". Comments to this paper can be submitted until 6th June 2017.

Email address for submissions: qwp@ema.europa.eu

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Handling of Reports of Suspected Quality Defects in Medicinal Products

GDP Compliance : EMA Active substances and medicinal products shall be distributed in accordance with good distribution practices. Member States shall enter the certificates of good distribution practices which they issue in the Union database (EudraGMDP) in accordance with Art. 111(6) of the Directive 2001/83/EC as amended. The Community formats for the GDP Certificate for Medical Products and for active substances are published in the Compilation of Community Procedures, which can be found at the following location: The EudraGMDP Database contains GMP and GDP Compliance and Non-Compliance reports. So far a lot of GMP information has been published by the EU authorities but less about GDP compliance. Every EU Member State Inspectorate is asked to publish their GMP and GDP Inspection results. This will allow other authorities and industry to check the compliance status of certain companies. A number of EU authorities have not published their GDP data information yet. However, progress can be seen also with regard to GDP compliance certificates and GDP non-compliance reports. From January 2016 until today six GDP non-compliance reports have been published. The Czech authority published three, the Danish authority two and a German inspectorate one GDP non-compliance report. The current reports are not very detailed. However, some information can be found. For instance, for the company Ya Medicare in Winsen Germany the inspectors state: "The company has in general failed to comply with good distribution practice as they did not use the described quality system. The company has written procedures but was not able to show an adequate documentation for acting according to the procedures. Further the company does not have relevant documentation for storage and transport under correct temperature, a system for ensuring that they only obtain their supplies of medicine from companies with a valid WDA/MIA or a system for ensuring that they only supply medicines to companies with a valid WDA or a valid license to supply medicinal products to the public." The information provided in the report is very helpful in order to understand the nature of the non-compliance. 1. Introduction  1.1 One of the main purposes of the GMP/GDP Inspectors Working Group is to establish and maintain a system for mutual recognition of national inspections in respect of the manufacture and, where relevant, wholesale distribution of medicinal products and for the administrative collaboration between Member States (MS) of the European Economic Area (EEA). The general requirements for national pharmaceutical inspectorates are to fulfil the requirements of national legislation and of the relevant European Directives for EEA countries. Specific obligations of inspections as contained in national law and if any European Directives must be included in the national Inspectorate’s quality systems.  1.2 This document outlines the quality system requirements for GMP pharmaceutical inspectorates. It is intended that each GMP pharmaceutical inspectorate uses the document as the basis for developing and implementing its quality system and for preparing the quality manual. In addition to providing a basis for self-assessment and a reference document for use by external assessors, establishing and maintaining an effective quality system will generate confidence within and between GMP national pharmaceutical inspectorates in the assessment of compliance with good manufacturing practice and/or good wholesale distribution practice. 1.3 National GMP pharmaceutical inspectorates, the European Commission (EC), the European Medicines Agency (EMEA) and the pharmaceutical Inspection Cooperation Scheme – (PIC/S) should co-operate with one another in exchanging experiences in the maintenance and operation of quality systems and in the further development of this document.  1.4 Only on voluntary basis, this document could be useful for (other) inspectorates assessing compliance with GXP or for the inspection of pharmacies.  1.5 In preparing this text, the working group was advised by: EN ISO/IEC 17020:2005 General criteria for the operation of various types of bodies performing inspections; EN ISO/IEC 17023:2006 General requirements for bodies operating assessment and certification/ registration of quality system; ISO 9001-2000 Quality management systems-Requirements;  ISO 9004-2000 Quality management systems: guidelines for performance improvements;  ISO 19011 : 2002 Guidelines for quality and/or environmental managerial systems auditing;  PI 002-1 : 2000 Recommendations on quality system requirements for pharmaceutical inspectorates; Compilation of Community Procedures on Inspections and Exchange of Information  EMA/572454/2014 Rev 17 Page 7/253 May 2001 Revised Compilation of Community procedures on administrative collaboration and harmonisation of inspections; 1998 Proceedings of the PIC-PIC/S seminar on quality systems for pharmaceutical inspectorates. Handling of Reports of Suspected Quality Defects in Medicinal Products Procedure for Handling Rapid Alerts Arising from Quality Defects Download:  Full guideline Quality Systems Framework for GMP Inspectorates

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EMA issues new Guideline on "Chemistry of Active Substances"

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline "Chemistry of Active Substances" (3AQ5a) from 1987 and the "Guideline on the Chemistry of New Active Substances" from 2004. Because both Guidelines' content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document  entitled "Guideline on the chemistry of active substances" (EMA/454576/2016), which was issued on 21 November.

The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline "already existing" ingredients are those that are used in a product already authorized in the EU.

In detail the information and data regarding the substance have to be included in the following chapters of the CTD:

3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.

3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.

3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.

3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.

3.2.S.2.5: Information on Process Validation

3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.

3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.

3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance's specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance's specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.

3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia - counting as completely qualified reference standards - are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.

3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance's quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.

3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.

The Guideline's provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a "traditional" way or according to the "enhanced" approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.

The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.

The Guideline "Guideline on the chemistry of active substances" (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.

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EMA revises Guideline on Process Validation for Finished Products

EMA revises Guideline on Process Validation for Finished Products

The EMA (European Medicines Agency) has published the revised version of its “Guideline on process validation for finished products – information and data to be provided in regulatory submissions“ on 21 November 2016.

 

The amendment is considered to be minor and only comprises an update to the definition for “on-line measurement" included in the glossary. A consultation phase was considered to be unnecessary as the document is not intended as a full revision of the guideline.

Source:

EMA: Guideline on process validation for finished products

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Comprehensive Overview of global Initiatives on Medicine Regulation published

The European Medicines Agency (EMA) has published an overview of existing international regulatory initiatives for human medicines, like for example International Council for Harmonisation (ICH), Pharmaceutical Inspection Co-operation Scheme (PIC/S), International Pharmaceutical Regulators Forum (IPRF) and International Coalition of Medicines Regulatory Authorities (ICMRA) members.

The report entitled  (click to download)  "Connecting the dots - Towards global knowledge of the international medicine regulatory landscape: mapping of international initiatives" also lists the respective international projects and details on the number and scope of global initiatives.

The aim of the mapping exercise is to raise awareness of ongoing international regulatory activities, help establish a basis for a more strategic coordination to avoid duplication of efforts, and identify possible gaps.

In the conclusion, EMA mentions that there is "a myriad of initiatives but no strategic coordination". So these mappings and analyses should "strongly support the need for a global strategy to support cooperation between international medicines regulators, to help avoid an overlap of activities and make resources available for areas where gaps still exist."

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Attention All: Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group 2015

EMA's GMP/GDP Inspectors Working Group has published its annual report. This group of senior GMP Inspectors meets on a regular basis four times a year. The group consists of representatives of the GMP inspectorates of the European Economic Area Member States, a representative from the European Commission (DG Enterprise and Industry) and observers from EDQM, the inspectorates of the countries accessing to the EU and MRA partner countries. The Sector provides the chair and secretarial support for these meetings.

The meetings consider new and revised GMP related guidance, normally developed by drafting groups, work related to Mutual Recognition Agreements, how new legislation impacts GMP inspection activity and harmonisation of GMP inspections. The outcome of the work is summarised in annual reports. The reports also briefly summarise number and outcome of GMP inspections in third countries and the status of the current Mutual Recognition Agreements (MRAs) and other agreements on GMP.

      A breakdown of the figures corresponding to those third countries where EEA authorities conducted the highest number of GMP inspections in 2015 is given below. They have been split according to their outcome (i.e. GMP certificates vs. non-compliance statements).

2015

Country             GMP certificates            GMP Non-compliance statements

India                            135                                           6

United States               110                                          1         

China                            72                                            6         

Turkey                          18                                            0

Japan                            13                                           0

Taiwan                          09                                           0

ROW*                           79                                           0

Download full report: Please see the Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group 2015 for more detailed information.

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The Guideline on good pharmacovigilance practices (GVP) now comprisese several updates:

The Guideline on good pharmacovigilance practices (GVP) now comprisese several updates:

On 8 August 2016, draft revision 2 of Module VI on management and reporting of adverse reactions and draft revision 1 (major revision) of Module IX on signal management with its Addendum I (Methodological Aspects of Signal Detection from Spontaneous Reports of Suspected Adverse Reactions) were released for public consultation until 14 October 2016.

The draft documents contain the following updates and amendments, which are highlighted in the respective documents:

GVP Module VI: 

• Update on the electronic reporting modalities of ICSRs (Individual Case Safety Report) under the new ICH-E2B(R3) format;
• Update on ICSRs reporting, following-up, duplicate detection, data quality management, in line with the provisions in Art. 24 of Reg. (EC) No 726/2004, Art. 107 and 107a of Dir. 2001/83/EC;
• Update on the validation of ICSRs based on patients and reporters identifiability;
• Update on the management of ICSRs described in the scientific literature;
• Update on the collection of information on patient’s age;
• Guidance on the management of suspected adverse reactions reported through medical enquiry and product information services;
• Guidance on the management of reports from post-authorisation efficacy studies;
• Transfer of the guidance on Emerging Safety Issue to GVP Module IX;
• Editorial amendments to align the format with other GVP Modules.

GVP Module IX with its new Addendum I:

• Revised definition and process for emerging safety issues, previously addressed in GVP Module VI (IX.C.3.1.);
• Streamlined information on scientific aspects of signal management (IX.B.2. to 4.), statistical aspects now addressed in Addendum I;
• Clarifications on terminology (IX.A.1.), roles and responsibilities (IX.C.1.) and processes (IX. Appendix 1);
• Criteria for access by marketing authorisation holders to case narratives held in EudraVigilance, with reference to Revision 2 of the EudraVigilance Access Policy (IX.C.2.1.);
• Updated guidance on the periodicity of monitoring of EudraVigilance data (IX.C.2.2.);
• Procedural options for signals validated by marketing authorisation holders (IX.C.3.).

On the following questions the agency seeks specific feedback:

• Are the proposed criteria for access to case narratives held in EudraVigilance by marketing authorisation holders acceptable (see IX.C.2.1.)?
•  Are the recommendations regarding the frequency of monitoring of EudraVigilance data acceptable (see IX.C.2.2.)?
• Are the proposed timelines and modalities for communication of emerging safety issues and validated signals by marketing authorisation holders clear and acceptable (see IX.C.3.)?

Additionally, the Product- or Population-Specific Considerations P.II on biological medicinal products were published as final on 15 August 2016, having been amended in the light of their public consultations.

Furtheremore, Module VIII – Post-authorisation safety studies (Rev 2) and Module VIII Addendum I – Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev 2) were published as final on 8 August 2016.

For more Information please visit the EudraLex - Volume 9 

Pharmacovigilance Guidelines website

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News about GMP/cGMP

The European Commission has published a revised Version 7 of its Question and Answers Document that sets out frequently asked questions on importation of active substances for medicinal products for human use. This document is continuously updated and further supplemented.

With this new version, Q&A 35 was added to clarify the requirements in case of importation of active substances released for sale before the expiration date of their written confirmation but only imported into the EU once the written confirmation had been expired. The detailed answer can be summarized to the extent that

“It is legitimate to consider that the guarantees of equivalence provided by the written confirmation apply to any API batch in the scope of the written confirmation which was released for sale within the period of validity of the written confirmation, even if not exported in that time period.”

This is acceptable provided that the data unequivocally proves the whole process and that a solid justification of why a valid written confirmation is not available is given. Furthermore, a minor editing of Q&A 10A and 29A was carried out and Q&A 29B was deleted.

Source:

EC: Medicinal Products for Human Use

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EMA - requirements for quality documentation concerning biological investigational medicinal products

Already in 2012, the European Commission published a guideline on the quality documentation for IMP in clinical trials. Now on 23 June, the EMA issued a draft "Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials". It is open for public consultation from 1 July until 31 December 2016. The new draft should be read in connection with Regulation (EU) No. 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, which came into force on June 20, 2014.

The EMA summarizes the scope of the document as follows:

"This guideline addresses the specific documentation requirements on the biological, chemical and  pharmaceutical quality of IMPs containing biological / biotechnology derived substances. Moreover, this guideline lists, as regards documentation on the biological, chemical and pharmaceutical quality of the IMP, examples of modifications which are typically considered as 'substantial'. The guidance outlined in this document applies to proteins and polypeptides, their derivatives, and products of which they are components (e.g. conjugates). These proteins and polypeptides are produced from recombinant or non-recombinant cell-culture expression systems and can be highly purified and characterised using an appropriate set of analytical procedures. The guideline also applies to Auxiliary Medicinal Products containing these proteins and polypeptides as active substances.

The principles may also apply to other product types such as proteins and polypeptides isolated from tissues and body fluids. Advanced Therapy Medicinal Products are excluded from this guideline."

Related to the fact that the most available guidance documents for biological products address the quality requirements for marketing authorisation applications and are often not really applicable for a clinical trial application, this document outlines principles which should be taken into consideration during product development. But the guidelines on Virus safety evaluation of biotechnological investigational medicinal products (EMEA/CHMP/BWP/398498/05) and Strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (EMEA/CHMP/SWP/28367/07) should be read in conjunction.

More details and the information for submitting comments can be found directly in the Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials.

Source: ECA Academy

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Compilation of Community Procedures on Inspections and Exchange of Information guideline

GDP Compliance 

Active substances and medicinal products shall be distributed in accordance with good distribution practices. Member States shall enter the certificates of good distribution practices which they issue in the Union database (EudraGMDP) in accordance with Art. 111(6) of the Directive 2001/83/EC as amended.

The Community formats for the GDP Certificate for Medical Products and for active substances are published in the Compilation of Community Procedures, which can be found at the following location: Click Here for Download /Open in pdf

Compilation of Community Procedures on Inspections and Exchange of Information

Introduction The Compilation of Community Procedures on Inspections and Exchange of Information, formerly known as the Compilation of Community Procedures on Administrative Collaboration and Harmonisation of Inspections, is a tool for facilitating co-operation between the GMP inspectorates of the Member States and a means of achieving harmonisation. 

The procedures within it provide the basis for national procedures that form part of the national GMP inspectorates’ quality systems. These quality systems are based on a framework laid down in one of the documents of the Compilation. In July 2010 documents connected with Good Distribution Practice (GDP) inspections started to be added to the Compilation. The contents of the Compilation of Procedures are constantly updated developed and agreed, under the co-ordination of the European Medicines Agency, by representatives of the GMP 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 European Medicines Agency. The Heads of Medicines Agencies have agreed to the setting up of a joint audit programme of GMP inspectorates to maintain mutual confidence in the GMP inspection systems of each member state by the other member states, and the Compilation provides criteria on which the audits are based. Member states are obliged to take account of the Compilation of Procedures by virtue of Art. 3(1) of Directive 2003/94/EC. Until such time as the corresponding GMP directive for veterinary medicinal products, Directive 91/412/EEC, is amended accordingly, GMP Inspectorates dealing exclusively with veterinary medicinal products have voluntarily agreed to abide by it, although it is recognised that the formats for inspection reports, manufacturing authorisations and GMP certificates are of a binding nature by virtue of Art. 51 of Directive 2001/82/EC, as amended.

Quality Systems Framework for GMP Inspectorates Table of contents: 

• Introduction 

• Purpose 

• Scope

 • Definitions

 • Quality Manual

 • Administrative Structure

 • Organisation and Management

 • Documentation and Change Control 

• Records

 • Inspection Procedures 

• Inspection Resources 

• Internal Audit 

• Quality Improvement and Corrective/Preventive Action 

• Complaints 

• Issue and Withdrawal of Licenses and GMP Certificates

 • Handling Suspected Quality Defects and Rapid Alert System 

• Liaison with OMCL 

• Sub-Contracting and Assessing

 • Publications

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Source: EudraGMP

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