AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?

 regulatory  Comments Off on EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?
Jan 172017
 

 

 

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In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.

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http://www.gmp-compliance.org/enews_05736_EMA-publishes-Q-A-on-Health-Based-Exposure-Limits—Does-the-1-1000-dose-criterion-come-again-into-play-in-Cleaning-Validation_15560,15661,15963,Z-VM_n.html

In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.

The document altogether comprises five pages with 14 questions and answers.

The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.

Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.

There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.

The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.

Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.

At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.

 

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///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion,  Cleaning Validation,

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EMA issues new Guideline on “Chemistry of Active Substances”

 EMA, regulatory  Comments Off on EMA issues new Guideline on “Chemistry of Active Substances”
Dec 222016
 

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The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

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.

///////////////EMA, Guideline,  chemistry of active substances

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EMA/ FDA Mutual Recognition Agreement on drug facility inspections moving forward

 regulatory  Comments Off on EMA/ FDA Mutual Recognition Agreement on drug facility inspections moving forward
Nov 222016
 

 

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EMA/ FDA Mutual Recognition Agreement moving forward
A possible agreement between the EMA and the US FDA on mutual recognition agreement on drug facility inspections could already be signed in January 2017.

http://www.gmp-compliance.org/enews_05650_EMA–FDA-Mutual-Recognition-Agreement-moving-forward_15642,15660,15656,Z-QAMPP_n.html

A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections could already be signed in January 2017. This is noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections by January 2017 is under consideration.”

But, according to the Commission, some issues are still not resolved – like, for example, the exchange of confidential information and the inclusion of veterinary products in the scope of the text.

The “Report of the 15th Round of Negotations for the Transatlantic Trade and Invesment Partnership” summaries the 15th round of negotiations for the Transatlantic Trade and Investment Partnership (TTIP) from 3rd to 7th October 2016 in New York.

////////EMA, FDA,  Mutual Recognition Agreement, drug facility inspections

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Practical Implementation of the Control of Elemental Impurities: EMA’s new Guideline Draft

 regulatory  Comments Off on Practical Implementation of the Control of Elemental Impurities: EMA’s new Guideline Draft
Jul 222016
 

 

One and a half year after its publication, the ICH Q3D guideline still raises many questions. The EMA has recently published a guideline draft aiming at clarifying the practical implementation of ICH Q3D. Read more here about what is expected in a marketing authorisation application or in an application for a CEP with regard to risk assessment and the control of elemental impurities in APIs and medicinal products.

http://www.gmp-compliance.org/enews_05481_Practical-Implementation-of-the-Control-of-Elemental-Impurities-EMA-s-new-Guideline-Draft_15339,15429,15332,S-WKS_n.html

The “ICH Q3D Guideline for Elemental Impurities” was published in December 2014 as Step 4 document and released in August 2015 under No EMA/CHMP/ICH/353369/2013 as EMA’s Scientific Guideline. The guideline came into effect in June 2016 for all medicinal products currently underlying a marketing authorisation procedure (new applications).

In the meantime, it became clear that implementing in practice the requirements of this guideline has been so complex and led to some marketing authorisation procedures being delayed. The ICH has already reacted to the situation and published 7 training modules on its website. Moreover, a concept paper announces a question & answer document.

On 12 July 2016, the draft of an EMA’s guideline entitled “Implementation strategy of ICH Q3D guideline” (EMA/404489/2016) was published. The purpose of the document is to provide support for implementing ICH Q3D in the European context.

The draft comprises three chapters addressing the most important elements in relation with the implementation of the ICH Q3D requirements. The chapter “1. Different approaches to Risk Management” starts describing the two fundamental approaches to the performance of a risk assessment and the justification for a control strategy with regard to elemental impurities:

Drug Product Approach
Here, batches of the finished product are scanned by means of analytical (validated!) procedures to develop a risk-based control strategy. If – with this approach – the omission of a routine testing has to be justified, the authority expects a detailed and valid justification though, and not just analytical data from a few batches.

Component Approach
The guideline draft clearly gives its preference to this approach. The respective contribution of the different components of a medicinal product is considered with respect to the potential total impurity profile and compared to the PDE value from the risk assessment. All potential sources of impurity, for example from production equipment or from excipients of natural (mined) origin have to be considered in this assessment. This particularly applies to outsourced APIs; here, all pieces of information available from Active Substance Master Files (ASMFs) or Certificates of Suitability (CEPs) have to be used. Substances with a Ph.Eur. monograph should always comply with the elemental impurities limits of the corresponding monograph.

The chapter “2. Particulars for Intentionally Added Element(s)” deals with the common practice in many organic syntheses to add elements to increase the specificity of the chemical reaction and the yield. It is particularly critical when the last step of an API synthesis just before the end product uses a metal catalyst. In such a case, the authority expects a convincing evidence that the catalyst is purged to levels consistently below the control threshold (<30% of the PDE) by means of appropriate methods. All details about the API synthesis including the fate of the metals intentionally added have to be consistently described and documented in the marketing authorisation application or in the application for a CEP. If the routine testing of an elemental impurity is needed, the API manufacturer may determine a specification. This information will be required by the medicinal product manufacturer for his overall risk assessment.

The chapter “3. ASMF/CEP: dossier expectations and assessment strategy” explains who has to submit the risk assessment necessary for an ASMF or a CEP and how the dossier will be processed by the assessor of the regulatory authority. Basically, two scenarios are possible:

1. The API manufacturer submits a summary of a risk assessment/management for elemental impurities
Such information flows in the overall risk assessment of the medicinal product manufacturer and is assessed by the quality assessor/ CEP assessor within the marketing authorisation procedure. All data and documents used for the risk assessment should also be available for a GMP inspection.

2. The API manufacturer doesn’t perform any risk assessment/ management.
The regulatory authority basically expects a detailed description of the API synthesis including data on all metal catalysts used. This as well as the analytical routine controls on elemental impurities performed by the API manufacturer will also be assessed by the quality assessor/ CEP assessor. Nevertheless, the assessor won’t make a final conclusion in the ASMF or CEP assessment report with regard to the compliance with ICH Q3D. This will be done within the marketing authorisation procedure for the medicinal product.

The guideline draft can be commented on until 12 August 2016.

///////////ICH Q3D, Control of Elemental Impurities,  EMA, control of elemental impurities in APIs

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EMA reviews Medicines manufactured at U.S. Company

 regulatory  Comments Off on EMA reviews Medicines manufactured at U.S. Company
Jul 142016
 

Following the issuance of two Non-Compliance Reports for two sites of the US based company, EMA has started a review of medicines manufactured by Pharmaceutics International Inc., USA.

The European Medicines Agency (EMA) has started a review of medicines manufactured by Pharmaceutics International Inc., USA. This follows the issuance of two Non-Compliance Reports for two sites of the US based company after an inspection in February 2016 conducted by the MHRA (the medicines regulatory agency in the United Kingdom) which highlighted several shortcomings in relation to good manufacturing practice (GMP).

Pharmaceutics International Inc. manufactures the centrally authorised medicine Ammonaps (sodium phenylbutyrate) and is also the registered manufacturing site for some other medicines that have been authorised through national procedures in the European Union (EU).

This inspection which was a follow-up to an inspection in June 2015 aimed to assess whether corrective measures agreed previously had been appropriately implemented. It found that shortcomings remained, which included insufficient measures to reduce the risk that traces of one medicine could be transferred to another (cross-contamination), as well as problems with the way data were generated and checked and deficiencies in the systems for ensuring medicines’ quality (quality assurance).

EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.

There is no evidence that patients have been put at risk by this issue. However, as a precautionary measure, medicines from this site will no longer be supplied to the EU unless they are considered to be ‘critical’ to public health. Criticality will be assessed by national medicines regulatory agencies for their territories, taking into account alternatives and any impact of shortages on patients. In case where a medicine manufactured at this site is considered not critical in a member state it will no longer be supplied in this member state and any medicine remaining on the market will be recalled.

Source: EMA Press Release

Pharmaceutics International Inc., USA

/////////// EMA,  Medicines,  manufactured, U.S. Company, Pharmaceutics International Inc., USA

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EMA publishes Q&A on data required for sterilized primary packaging materials used in aseptic manufacturing processes

 Uncategorized  Comments Off on EMA publishes Q&A on data required for sterilized primary packaging materials used in aseptic manufacturing processes
May 192016
 

The European Medicines Agency, EMA, recently published questions and answers on what data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process. Read more about “What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?“.

http://www.gmp-compliance.org/enews_05330_EMA-publishes-Q-A-on-data-required-for-sterilized-primary-packaging-materials-used-in-aseptic-manufacturing-processes_15303,15493,15615,Z-PKM_n.html

The European Medicines Agency, EMA, recently published questions and answers on quality of packaging materials (H+V April 2016):

“3. What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?
Terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation of the packaging materials takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity1. When GMP certification is not available, certification that the sterilisation has been conducted and validated in accordance with the following ISO standards would be considered to provide an acceptable level of sterility assurance for the empty primary container:

  • I.S. EN ISO 20857:2013 Sterilization of Health Care Products – dry Heat – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 20857:2010);
  • I.S. EN ISO 11135:2014 Sterilization of Health-care Products – Ethylene Oxide – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11135:2014);
  • I.S. EN ISO 17665-1:2006 Sterilization of Health Care Products – Moist Heat – Part 1: Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS 17665-2:2009 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1;
  • I.S. EN ISO 11137-1:2015 Sterilization of Health Care Products – Radiation – Part 1: Requirements for Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11137-1:2006, Including 1:2013);
  • I.S. EN ISO 11137-2:2015 Sterilization of Health Care Products – Radiation – Part 2: Establishing the Sterilization Dose (ISO 11137-2:2013);
  • I.S. EN ISO 11137-3:2006 Sterilization of Health Care Products – Radiation – Part 3: Guidance on Dosimetric Aspects.

It is the responsibility of the user of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of packaging materials. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This should be checked during inspections. The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

Dossier requirements:

The following details regarding the sterilisation of the packaging components should be included in the dossier:

1. The sterilisation method and sterilisation cycle;
2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;
3. The name and address of the site of sterilisation and, where available details of GMP certification of the site. Where the component is a CE-marked Class Is sterile device (e.g. sterile syringe), confirmation from the manufacturer that the component is a Class Is sterile device, together with a copy of the declaration of conformity from the Notified Body will suffice.

In the absence of GMP certification or confirmation that the component is a CE-marked Class Is medical device, certification that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.
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1Sites located in the EU which perform sterilisation of primary packaging components only are not required to hold a Manufacturer’s/Importer’s Authorisation (MIA). Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a MIA in relation to these activities.”

Source: European Medicines Agency – Quality of medicines Q&A: Part 2 – Packaging.

 

///////////EMA,  Q&A, data, sterilized primary packaging materials,  aseptic manufacturing processes

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EMA’s new Draft Guideline on the Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers

 regulatory  Comments Off on EMA’s new Draft Guideline on the Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers
May 122016
 

 

For medicinal products administrated in sterile form, the process to reduce the microbial level is a critical manufacturing step with regard to quality. The EMA has recently published the draft of a guideline on that topic which contains a range of clarifications. Read more about the coming requirements on sterilisation of medicinal products, APIs, excipients and final containers

see

http://www.gmp-compliance.org/enews_05350_EMA-s-new-Draft-Guideline-on-the-Sterilisation-of-Medicinal-Products–APIs–Excipients-and-Primary-Containers_15435,S-WKS_n.html

As referred to in the European Pharmacopoeia, the procedure for terminal sterilisation of a medicinal product, an API, or an excipient is generally the method of choice. Yet, this might be difficult in many cases for product stability reasons. That’s why other microbial reduction processes can be used like sterilising filtration or aseptic processing. So far, there has been some uncertainty about these methods and their acceptance in a marketing authorisation procedure or a variation application, and about which data have to be submitted.

EMA’s new draft guideline entitled “Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container”  from April 2016 contains clear provisions with regard to the acceptance of alternative sterilisation processes by the European authorisation authorities. Those provisions apply to chemical and biological medicinal products for human and veterinary use as well as the respective APIs and excipients, but aren’t applicable for immunological veterinary medicinal products.

The document describes the requirements on sterilisation of medicinal products, APIs, excipients and primary containers, as well as on the choice of the method of sterilisation. Besides, the document contains two decision trees for the selection of the sterilisation method for products in diverse galenic forms.

Please find hereafter a summary of most important aspects in this chapter:

Manufacturing of sterile medicinal products
The conditions and physical parameters for the following processes are described in detail:

  • Steam sterilisation
  • Dry heat sterilisation
  • Ionisation radiation sterilisation (here reference is made to the Note for Guidance “The use of Radiation in the Manufacture for Medicinal Products“, ISO 11137 and Ph. Eur. Chapter 5.1.1)
  • Gas sterilisation (with ethylene oxide,  ethylene chlorhydrin, etc.)
  • Sterile filtration
  • Aseptic processing

Basically, the following rules apply to all processes:

  • The choice of the sterilisation method has to be justified.
  • The method must be validated.
  • The method described in the corresponding general monograph of the European Pharmacopoeia has to be used. All deviations have to be justified.
  • The procedures for all sites (including outsourced activities) where sterilisation is performed have to be documented (CTD module 3, chapters 3.2.P.2 and 3.2.P.3).

Manufacturing of sterile APIs and excipients
The document clarifies that the requirements laid down in Part II of the EU GMP Guide are only applicable for the manufacture beginning with the starting material up to the finished API, immediately prior to sterilisation. The sterilisation step performed on the API is considered to be a step in the manufacture of the medicinal product. As a consequence, each manufacturing establishment which performs sterilisation of an API requires a manufacturing authorisation, a GMP certificate and thus aQualified Person too. This also applies to establishments which manufacture sterile excipients. APIs and excipients with a Certificate of Suitability (CEP) are also covered by this regulation.

Selection of the sterilisation method
The following principles apply:

  • According to Ph. Eur., general chapter 5.1.1, the terminal sterilisation step should be made in the final container whenever possible.
  • When sterilisation by heat is not possible because of temperature sensitivity of the product, alternative methods or aseptic processing may be used if they are properly validated. Terminal steps for the reduction of the microbial level are also possible as long as they are not used to compensate for poor aseptic manufacturing practice.
  • A change (shortening) in shelf-life or storage conditions caused by the terminal sterilisation step is not in itself a reason to allow aseptic processing unless the new storage conditions or shelf-life would cause problems or restrictions in the use of the product.
  • An increase in impurity levels or degradation products upon terminal sterilisation doesn’t directly lead to the acceptation of aseptic processing. The risks induced by an increased level of impurities should be balanced with the risks induced with an aseptic manufacturing method (e.g. characteristics of the degradation products vs. posology of the medicinal product). Attempts performed to determine sterilisation conditions to give acceptable impurity levels and to simultaneously achieve a microbial reduction of at least 10-6 have to be described in the quality dossier.
  • Under specific conditions, aseptic processing may be accepted even if terminal sterilisation of the product itself would be possible, e.g. in the case of eye drops in polyethylene containers enabling administration of single drops or pre-filled pens. Here, terminal sterilisation of the product would destroy the final container.
  • The considerations for the choice of the container should be described in the dossier also in the case of heat-sensitive final containers. Here, the search for materials which come through terminal sterilisation has priority. For example, polypropylene is more resistant than polyethylene. The choice for the final container has to be justified.
  • Large volume parenterals should be terminally sterilised whenever possible.

In general, the regulatory authorities will expect a detailed justification for the selection of the sterilisation method or the aseptic processing in the form of a benefit/risk analysis.

The essence of the requirements described in the chapters of this guideline can be found in the two decision trees for sterilisation of products in diverse administration forms (aqueous liquid; non-aqueous liquid, semi-solid, dry powder).

The deadline for comments on this Draft Guideline Sterilisation of the medicinal product, active substance, excipient and primary container ends on October, 13th 2016.

///////////////EMA,  new Draft Guideline, Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers

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EMA publishes finalised Process Validation Guideline for Biotech Products

 regulatory  Comments Off on EMA publishes finalised Process Validation Guideline for Biotech Products
May 052016
 

 

Approximately two years ago the EMA published a draft guideline on process validation for the manufacture of biotech products. Now the final guideline has been published under the title “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission“.

READ

http://www.gmp-compliance.org/enews_05342_EMA-publishes-finalised-Process-Validation-Guideline-for-Biotech-Prodcts_15435,15373,15298,15250,Z-VM_n.html

Approximately two years ago the EMA published a draft guideline on process validation for the manufacture of biotech products. Now the final guideline has been published under the title “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission”.

The scope of the guideline is to provide guidance on the data to be included in a regulatory submission to demonstrate that the active substance manufacturing process is in a validated state. The guideline focuses on recombinant proteins and polypeptides, their derivates, and products of which they are components (e.g. conjugates). But it is explicitly mentioned that the principles could also be applied to vaccines or plasma-derived products and other biological products, as appropriate.

Process validation is mentioned as life cycle, comparable to Annex 15 and to the EMA guideline on process validation for finished products . Also comparable to both, the guideline offers a traditional or an enhanced  (with reference to ICH Q 11) approach to process validation. A combination of both approaches is possible as well. This “hybrid approach” is in line with the other new European process validation guidelines, too.

Process validation is divided into two parts:

  • process characterisation, where the commercial manufacturing process is defined

and

  • process verification, where the final manufacturing process as established based on process evaluation studies performs effectively in routine manufacturing.

Process characterisation itsself is also divided into two parts:

  • process development, which includes studies to reach a potential design of a future manufacturing process

and

  • process evaluation which includes studies on small and/or commercial scales, providing evidence that the complete manufacturing process has been appropriately designed to design the full operating ranges of the manufacturing process.

It is explicitly mentioned that subsequent to succesfull process validation product quality and process performance must be maintained in a state of control during routine production. This ongoing process verification is normally not part of submission data, with the exception of e.g. niche products, which could not be fully validated at the time of the regulatory submission.

There is no number of validation runs mentioned in this guideline and concurrent validation could  be considered only in exceptional circumstances (e.g. medical need is mentioned) and after consultation with the regulatory authorities.

Please find further information in the “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission”

/////EMA,  publishes,  finalised,  Process Validation Guideline,  Biotech Products

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GMP Oversight of Medicines Manufacturers in the European Union

 regulatory  Comments Off on GMP Oversight of Medicines Manufacturers in the European Union
Apr 212016
 

 

 

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

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.

Legislation

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.

Training

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.

PIC/S

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.

Notes

*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

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Road map to 2015, The European Medicines Agency’s contribution to science, medicines and health

 EU, regulatory, Uncategorized  Comments Off on Road map to 2015, The European Medicines Agency’s contribution to science, medicines and health
Aug 182014
 

 

One of the European Medicines Agency’s long-term strategic goals is to foster researchand the uptake of innovative methods in the development of medicines.

READ………….Road map to 2015

The European Medicines Agency’s
contribution to science, medicines and health……………..http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101373.pdf

This helps the Agency to meet its objective of making safe and effective medicines available to patients in a timely manner, following evaluation using state-of-the-art methods.

The Agency also supports the development of new therapies and technologies by working with interested parties in the European Union (EU).

Activities at the Agency

In 2004, the Agency set up the European Medicines Agency/Committee for Medicinal Products for Human Use (CHMP) Think-Tank Group on Innovative Drug Development.

This group included Agency staff and members of the CHMP and its working parties. Its work focused on identifying scientific bottlenecks and emerging science in the development of medicines, both in industry research and development and in academia, and on generating recommendations for future activities at the Agency:

In 2008 the EMA and its Scientific Committees integrated the recommendations made by the Think Tank in its strategy for supporting innovative medicines developments. Key areas of action included the strengthening of the EU scientific network model, emphasis on communication during the lifecycle of medicinal products development and international activities. Overview of measures implemented in the period 2008-2010.

The recently published Road Map to 2015 further expands on the role the Agency plays to promote innovation in pharmaceuticals.

The Agency also contributes to the Innovative Medicines InitiativeExternal link icon (IMI). This is a public-private initiative that aims to speed up the development of better and safer medicines for patients:

Support for business

The Agency provides support for business on issues related to innovative medicines:

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