EDQM Training Webinars on the Ph. Eur. – Overview and Highlights
1. GENERAL CONCEPTS AND METHODS
European regulations for medicines: Place and role of the EDQM and the European Pharmacopoeia (Ph. Eur.)
In the first training webinar, the role and structure of the Council of Europe, the EDQM and European Pharmacopoeia (Ph. Eur.) within the EU regulatory framework were discussed. The European Directorate for the Quality of Medicines & HealthCare (EDQM) is a Council of Europe Directorate, based on the Convention on the Elaboration of a European Pharmacopoeia (PA, 1964), whose mission is to ensure access to good quality medicines and healthcare within the EU.
The Ph. Eur. is the official pharmacopoeia in the EU, and it is complemented by national pharmacopoeias for texts of national interest. The Ph. Eur. is one common compulsory standard within the EU which contains legally binding quality standards.
The Ph. Eur. has a network of 21 active groups of experts and 40 working parties who work on the elaboration and revision of texts. These groups of experts and working parties meet up to 3 times a year and consist of more than 800 experts who hail mainly from Competent Authorities, the Industry and Universities, and are mainly from the Ph. Eur. signatory states, but as of 2016 experts from outside those states have also formed part of the network.
General concepts in the European Pharmacopoeia: Theory and Rationale
An overview of how the pharmacopoeial monographs and texts should be used and interpreted was given. The importance of reading the General Notices in conjunction with the monographs and chapters was highlighted as these are complementary, and it was emphasized that the General Notices apply to all Ph. Eur. texts. When using an individual monograph, users should check if there is a general monograph applicable to that particular product, since some individual monographs do not contain any cross-reference to the general chapters. General monographs ‘per se’ are not mandatory, however, they do become part of the standard when referred to in the monograph. It was also highlighted that pharmacopoeial methods do not need to be validated by the analyst unless otherwise stated in the monograph or general chapter, and that Ph. Eur. monographs cover both human and veterinary use unless otherwise stated.
The webinar also delved into the use of alternative methods as opposed to Ph. Eur. methods. Ph. Eur. tests are considered reference methods which are authoritative in cases of doubt or dispute, and compliance with Ph. Eur. methods is required. Alternative methods may also be used but it is the users’ responsibility to demonstrate their suitability and ultimately the approval of the competent authorities is still required. The EDQM has highlighted that it is not responsible for the approval of alternative methods, however, a new general chapter on alternative testing is currently under elaboration.
General methods: Concrete examples
This part of the EDQM webinar focused on the General Methods modernization programme, through which the EDQM has worked to revise the Ph. Eur. General Methods, many of which had not been reviewed since their publication over 15 years ago. The aims of the programme were to shift from a reactive approach to a pro-active approach in the general methods, to include recent progress in analytical technology and produce a Pharmacopoeia which is scientifically state-of-the-art, to follow development in regulatory practice, to standardize the template of the general texts, to introduce and/or improve elements of equipment performance and qualification, to introduce and/or improve universal system suitability tests, to suppress toxic reagents or materials and to increase user-friendliness of the general methods.
Some of the new or newly revised General Methods that have been adopted include:
- X-ray fluorescence spectrometry (2.2.37)
- Optical rotation (2.2.7)
- Conductivity (International Harmonization) (2.2.38)
- Osmolality (2.2.35)
- Loss on drying (2.2.32)
- Infrared absorption spectrophotometry (2.2.24)
- UV/Visible spectrophotometry (2.2.25)
- Degree of coloration of liquids (International Harmonization) (2.2.2)
- Test for BET using recombinant factor C (2.6.32)
In the revised Loss on drying (2.2.32) general method, diphosphorous pentoxide (toxic and obsolete) has been replaced by molecular sieves as a drying agent. The definition of “constant mass” was added and a clarification of the requirements was included. The use of “high vacuum” was discouraged due to issues with availability of the equipment, and other equipment is now allowed with validation (e.g. microwaves, halogen lamps, etc.). For equipment qualification, sodium aminosalicylate dihydrate CRS has replaced amoxicillin trihydrate since Ph. Eur. 9.4. The changes in the loss on drying general method have had an impact on around 1100 monographs.
The revised UV/Visible spectrophotometry (2.2.25) general method has seen the addition of UV-Vis detectors used in liquid chromatography and in PAT applications and the equipment qualification section improved. Clarification of the requirements was added to provide a link to the intended use of the monograph. The general method was also updated to include fixed performance criteria but flexibility in the use of certified material. Another update to the general method includes the use of Nicotinic acid for equipment qualification CRS as an alternative to potassium dichromate for the test of absorbance accuracy and linearity.
A new general method for BET using recombinant factor C (2.6.32) has been adopted. The classical bacterial endotoxin test (2.6.14) is based on limulus amoebocyte lysate (LAL) from the endangered horseshoe crab, while the new Chapter 2.6.32 describes a method using recombinant factor C, a synthetic reagent, and fluorimetric detection with the aim to reduce the impact on the endangered animal. With respect to this new general method, the revised general text 5.1.10. Guidelines for using the test for bacterial endotoxins, clarifies the conditions for the introduction of rFC-based methods by users of the pharmacopoeia.
In this webinar the EDQM also announced that the following new and revised general methods are in the pipeline:
- Chromatographic separation techniques (2.2.46) (International harmonization)
- Determination of elemental impurities (2.4.20) (International harmonization)
- Balances (2.1.7)
- N-Nitrosamines in active substances (2.4.36) (Pharmeuropa 32.2)
- Raman spectroscopy (2.2.48) (Pharmeuropa 32.3)
The Chromatographic separation techniques (2.2.46) general method will provide definitions and calculation methods for common parameters such as peak retention time and resolution. It will define the bounds within which chromatographic conditions could be adjusted without revalidation, such as the composition of mobile phase, column length and particle size. The method will also provide universal system suitability parameters, which will not be repeated in individual monographs, such as the minimum S/N ratio at reporting threshold and the limits of symmetry factor, thus, these parameters will become a mandatory part of the monograph. The public consultation stage of this general method is complete, and the draft is now being further discussed within the Pharmaceutical Development Group (PDG) and with regulators. When the general method is adopted it will result in major changes, including the transfer to UHPLC, symmetry factor 0.8 to 1.8, and the harmonisation of parameters such as resolution calculation.
The Balances (2.1.7) general method was developed after repeated requests from users and a survey with stakeholders. The method applies to analytical balances only; balances used for manufacturing purposes lie outside the scope of this general method. The text is based on current available guidance to fit in the regulatory landscape and it includes recommendations for performance checks on sensitivity and repeatability, and also includes the definition of minimum weight.
The N-Nitrosamines in active substances (2.4.36) general method is currently published in Pharmeuropa 32.2 and is open for public consultation. It applies to angiotensin-II-receptor antagonists (sartans) containing a tetrazole group, including the Ph. Eur. monographs for valsartan, losartan potassium, candesartan cilexetil, irbesartan and olmesartan medoxomil. The method includes a limit test of 0.03 ppm and applies to seven N-Nitrosamines including NDMA, NDEA, NDBA, NMBA, NDiPA, NEiPA and NDPA. The general method contains three validated analytical procedures which rely on different chromatographic techniques (GC and LC) and mass spectrometry detection, therefore, catering for the needs of many quality control laboratories around the world.
Other new chapters that were newly published or adopted include:
- Scanning electron microscopy (2.9.52) (Ed. 10.0), which provides imaging and chemical characterisation capabilities to evaluate morphology, size, shape and elemental composition of pharmaceutical products.
- Process analytical technology (5.25) (Ed. 10.0), which describes a general approach to the integration of analytical techniques in the process environment.
- Recommendations on testing of particulate contamination: visible particles (5.17.2) (Supp. 10.3), which provides guidance on how users can establish that their product is “practically free from particles”.
- Multivariate statistical process control (5.28) (Supp. 10.4), which concerns analysis of data with potentially correlated variables and generation of control charts for control and improvement of manufacturing processes and is a tool for continuous manufacturing (CM) and real-time release testing (RTRT).
The EDQM also has recently added the following major projects to its work program:
- Implementation of pharmacopoeial methods (5.26): Guidance to assess the extent to which a pharmacopoeial method is suitable and adequately performing for its intended purpose given the actual conditions of use in the laboratory of concern.
- Comparability testing of alternative methods (5.27): Equivalence testing guidance for instances when a pharmacopoeial method is replaced by an alternative method for control purposes.
- General procedures for analysis of recombinant therapeutic mAbs (2.5.43, 2.5.44 & 2.7.26): Guidance on the development of general SEC and cIEF procedures for mAbs and biological assays for anti-TNF-alpha product class.
- Evaporative light scattering detection (2.2.62)
2. PH. EUR. MONOGRAPHS
Specific monographs on “Substances for pharmaceutical use” and on Finished Products (containing chemically defined APIs)
In this part of the webinar, an overview of the different sections of individual monographs was given. With respect to impurity testing it was highlighted that Ph. Eur. monographs are in-line with ICH Q3A and that new impurity profiles are controlled in-line with Directive 2003/63/EC. Inorganic impurities are controlled according to ICH Q3D Guideline for Elemental Impurities (general chapter 5.20). DNA reactive (mutagenic) impurities testing in the Ph. Eur. follows ICH M7 and is in-line with general monograph 2034 Substances for pharmaceutical use.
The EDQM currently has the 15 adopted and published finished product monographs. Another 26 finished product monographs with chemically defined active substances are also under elaboration.
The EDQM has also adopted a general policy paper on monographs of finished products “General principles for Monographs on Finished Products (FPs) containing chemically defined active substances”, and a draft (not currently approved) “Technical Guide for the elaboration of Monographs on Finished Products containing chemically defined active substances” derived from the general policy paper, which is still under discussion.
The dissolution test in FP monographs currently follows the general principles, however, the EDQM has indicated that discussions are underway with respect to possible revision of dissolution testing for finished product monographs. The EDQM has also highlighted that the Rosuvastatin tablets monograph is the first monograph adopted under the P1 (multi-source) procedure.
Impurity Control in the European Pharmacopoeia: Theory and practical examples
This part of the webinar focused on the control of organic impurities, inorganic impurities, volatile impurities, water and residual solvents as well as special groups of impurities, including genotoxic (DNA reactive) impurities and inorganic impurities subjected to Q3D.
Organic impurities are controlled via several general texts including the following:
- General monograph 2034 “Substances for pharmaceutical use”: This describes the general requirements for controlling organic and inorganic impurities, volatile impurities and DNA reactive impurities.
- General text 5.10: Control of impurities in substances for pharmaceutical use: This guidance helps to interpret the test for related substances, provides definitions, explanations and recommendations.
- General text 5.4: Residual solvents: In-line with ICH Q3C.
- General text 5.20: Elemental impurities: In-line with ICH Q3D.
Inorganic impurities are controlled by general tests such as sulfated ash, heavy metals (2.4.8 is now only for substances for veterinary use), specific tests like AAS, ICP or the general chapter 2.4.20.
Volatile impurities are controlled according to general text 5.4 and general chapter 2.4.24. Class 3 solvents may be controlled by loss on drying (up to 0.5 %), whereas water content is most often controlled by semi-micro determination, coulometry or loss on drying.
As of the 1st January 2016 DNA-reactive (mutagenic) impurities have been subject to ICH M7, and the respective control tests may be found in the test or production section of the monographs. These tests are described only when there is proof for genotoxicity (not based on structural alerts).
Elemental impurities are controlled via ICH Q3D which has been fully implemented in Ph. Eur. General Text 5.20. General monographs 2034 (Substances for pharmaceutical use) and 2619 (Pharmaceutical preparations) have been revised accordingly and the classical heavy metal tests have been deleted from individual monographs (excluding monographs for veterinary use). The EDQM has also highlighted that Chapter 2.4.20 “Determination of elemental impurities” is under revision and harmonization in the pharmacopoeial discussion group. The chapter will include a new concept whereby example procedures will be provided (ICPMS/OES), validation criteria provided (e.g. accuracy, range, precision), and provided that the validation criteria are fulfilled, users can choose their own method.
How to participate in the Elaboration of the European Pharmacopoeia
This part of the webinar focused on how users may participate in the elaboration of Ph. Eur. monographs. The policy for monograph elaboration is given in the “Technical Guide for the Elaboration of Monographs” which is available on the EDQM website. The EDQM highlighted the importance of participation and the need to regularly review and update existing texts and create new ones. The webinar also described how users may request a revision of a Ph. Eur. text and highlighted that any request should be backed up by sufficient data, including batch data and validated methods. Ph. Eur. member states should contact their National Pharmacopoeia Authority (address list available on the EDQM website and Pharmeuropa online), while users from outside the member states should contact the EDQM.
The EDQM expressed its wish to have a Pharmacopoeia Liaison Contact for each major manufacturer and/or user who would be responsible for channelling information and requests from manufacturer to EDQM and who would be a reception point for contact by the EDQM.
3. PH. EUR. REFERENCE STANDARDS AND DATABASES
European Pharmacopoeia Reference Standards (RS): Establishment and use of Ph. Eur. reference standards, handling, dispatch, where to find useful information and other practicalities
Various topics related to Ph. Eur. reference standards were discussed including terms and definitions, establishment and use of Ph. Eur. RS, RS for finished products monographs and for general methods.
The EDQM also described the process for handling and dispatching of Ph. Eur. reference standards. The EDQM’s online catalogue (https://crs.edqm.eu), which is updated daily, should be consulted before placing an order. The catalogue contains other important information such as the terms and conditions of supply, a list of new batches and new items and the RS that have been withdrawn from sale in the past 12 months. The EDQM requires certain additional necessary documentation from the user prior to purchase of precursors, psychotropics, narcotics and biological materials. The EDQM does not have any authorized distributors of reference substances, however, on its website it has provided a list of organisations or companies known to re-sell EDQM products.
Changes in storage/shipping conditions of RS will now be announced in advance, except in cases of quality assurance issues, and the change will be implemented on the 15th of the following month where possible.
The webinar also gave an overview of the labelling of RS, what is expected of users, proving validity of the RS, shipping and storage, and safety.
Find your way in Pharmeuropa, the Knowledge database & Ph. Eur. Online: Useful hints and other practicalities
Some of the topics discussed in this webinar include: accessing publications and databases on the EDQM website (https://www.edqm.eu/en/databases) and the Ph. Eur. Online (https://pheur.edqm.eu) which is the new platform for the 10th Edition and contains new features and direct access to complementary information through the Knowledge Database. Use of the new Pharmeuropa website released in January 2020 and the Knowledge Database which provides additional information on a substance or general text were also discussed.
4. CERTIFICATE OF SUITABILITY (CEP) PROCEDURE
General presentation of the Certification of Suitability (CEP) Procedure and Use of a CEP
An overview of the contents and use of a CEP were described. The EDQM emphasized that a chemical or a herbal CEP certifies that the quality of the substance is suitably controlled by the Ph. Eur. monograph with additional tests if necessary, while a TSE CEP certifies that the substance complies with the Ph. Eur. General Chapter 5.2.8 on minimizing the TSE risk and it does not certify that the quality of the substance is suitably controlled by a specific Ph. Eur. monograph. The Directorate has also emphasized that a CEP does not substitute a certificate of analysis, a QP declaration or a GMP certificate.
The EDQM highlighted that the re-test period on a CEP is optional but still highly recommended. When a re-test period is requested by the applicant, the stability data is assessed and once approved the re-test date is included in the CEP. However, in cases where a re-test period is not requested by the applicant the stability data are not assessed by the EDQM and the data will be considered during the assessment of the MA dossier.
The Directorate has also highlighted that its assessment is performed taking into account the ‘general’/common use of the substance, while specific uses should be addressed in the MA dossier. Also, a CEP may not address all the parameters relevant for the specific use in the finished product such as physico-chemical characteristics, the production section and stability data for a re-test period (if not included in the CEP), therefore, additional data might still be required.
How to build a successful CEP application and avoid frequent deficiencies
The process of granting a CEP was described in this webinar. The validation and evaluation processes carried out by the EDQM were also discussed. The EDQM also highlighted that information on how to avoid deficiencies in CEP applications is available in the reference documents PA/PH/CEP (04) 1 6R “Content of the dossier for chemical purity and microbiological quality” and PA/PH/CEP (16) 58 “Top Ten Deficiencies – New applications for certificates of suitability for chemical purity (2015-2016)”.
Development of a suitable control strategy for the control of process-related impurities was also detailed in the webinar. During the webinar the EDQM also stressed that it encourages CEP applicants to submit a risk management summary (RMS) in the CEP dossier, and that it is a requirement to include the detailed synthetic route of the substance in the submission, including information on metal catalysts or reagents used. The EDQM also noted its expectations on the dossier content in situations where a RMS is not included in the application.
Revisions and renewal of CEPs: Principles, frequent changes and sister files
The basic principles for maintaining a CEP were discussed including revision applications, quality changes related to the manufacture of the active substance and intermediates, changes to specifications, renewals and sister files.
The sister files procedure allows applicants to benefit from a fast-track procedure and harmonised assessments for the submission of similar CEP dossiers in the CEP Certification procedure. Further guidance on sister files is available in the EDQM’s “Guidance on Applications for “Sister Files” (PA/PH/CEP (09) 141 2R, November 2018)” document.
The EDQM inspection programme
In this webinar the inspection programme of API manufacturers in the framework of EDQM’s CEP procedure was described. The aim of these inspections is to ensure compliance with the CEP dossier, compliance with EU GMP Part II and Annexures as applicable, and to ensure compliance with Ph. Eur. monographs. The EDQM also shared the outcome of the inspections carried out during 2019: 33 on-site inspections were carried out in which four sites were found to be non-compliant. A further 21 sites were evaluated via GMP certificates issued by EU/EEA/MRA authorities (18 sites), statements of GMP non-compliance issued by EEA inspectorates were taken into account leading to actions on CEPs in 2 sites, and a distant GMP assessment of 1 site has resulted in the postponement of the re-assessment.