Updated 08/04/2025:
'EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances' section
This content applies to human and veterinary medicines.
The European Medicines Agency's (EMA) provides answers to frequently asked questions on good manufacturing practice (GMP) and good distribution practice (GDP), as discussed and agreed by the GMP/GDP Inspectors Working Group.
The guidance provided by the working group in the form of questions and answers (Q&As) provides additional interpretation of the European Union (EU) GMP guidelines and GDP guidelines published by the European Commission. The working group prepares these Q&As as the need arises.
EMA may remove individual Q&As when the European Commission updates relevant guidelines.
The product review is expected annually. Review timeframes can be appropriately adjusted based upon manufacturing and campaign duration with adequate justification. The timeframe criteria should be established in a SOP. The trending can include results gathered from the previous period to ensure its robustness. Even if no manufacturing has occurred in the review period, the quality and regulatory review should be conducted as per section 1.10 and include stability results, returns, complaints, recalls, deviations (including those arising from qualification and validation activities) and regulatory background. The review of the last PQR should also be conducted.
Metal could originate from raw materials as well as from equipment in manufacturing processes where metal parts could generate fragments due to the conditions of operation or damage to the equipment.
It is recommended that metal detection is used for processes prone to this.
In order to avoid routine use of metal detectors the company must demonstrate that it has identified and managed the risks such that the use of metal detectors for that particular process is not needed.
GMP inspectors have discussed the desirability of more than one batch number appearing on the packaging of medicinal products.
It is normal practice for companies to use a bulk batch number that is different from the finished product batch when the bulk is packaged as several sub-batches. There is normally an element in the numbering format common to the bulk batch and finished product batches that clearly ties these together. The difference normally takes the form of a suffix, prefix or both.
A matter of concern for the inspectors is when the bulk and finished product batch numbers are completely different and there is no obvious connection between the two. Even though the manufacturer has a system of traceability, the inspectors agree that this is an undesirable practice and should be avoided. The main reasons for this are:
It is accepted that there may be exceptional cases where multiple batch numbers are displayed on a pack, such as in combination product packages. Manufacturers are recommended to discuss individual cases with the relevant supervisory authority. In all cases, traceability must be maintained.
The supply chain for each active substance must be established back to the manufacture of the active substance starting materials. This should be documented and must be kept current. The risks associated with this supply chain should be formally documented. Control of each incoming consignment of active substance should include verification that it has been received from the approved supplier and approved manufacturer. The entire supply chain should be verified for a supplied batch periodically to establish a documented trail for the batch back to the manufacturer(s) of the active substance starting materials. The frequency of this verification should be based on risk.
Normally, such an approach should be avoided as each batch is made from the same initial quantity of material and should remain as an individual batch of finished medicinal product bearing a unique batch number. Therefore, any other approach should be thoroughly justified by applying the principles of Quality Risk Management (QRM) taking into account at least the following criteria:
Irrespective of the outcome of the QRM, such an approach can only be accepted if each individual batch of the combined "super batch" undergoes all the in-process control and finished drug product testing as specified in the marketing authorisation dossier.
In the event of a recall, the entire “super batch” should be recalled.
Medicinal products that are relabelled or repacked with the purpose of parallel trade should be in compliance with any specific national legislation or guidance in relation to the batch number(s) that are to be present on the parallel distributed traded packs.
In the absence of specific national legislation or guidance, the outer packaging should have only one batch number, as allocated by the parallel trader. This batch number allocated by the parallel trader should incorporate two components; (1) the batch number of the original pack and (2) a unique code identifying the repackaging/relabelling run. The code for the repackaging run may comprise numbers or letters or a combination of both. The parallel trader’s batch number should be such that Component 1 above (originator batch number) is followed by Component 2 (a code related to the repackaging/relabelling run on that batch). Any deviation from this approach should be presented to and should be authorised by the supervisory authority. The traceability between the original batch number and the parallel trader’s batch number should be documented in the manufacturer’s repackaging records.
In the case of human medicinal products, the unique identifier generated by the parallel trader when (re)placing safety features should reflect the 2 component batch number as described above. The link between the original batch numbers and parallel trader’s two component batch number should be maintained in the EU repositories system as per Article 34(4) of Commission Delegated Regulation (EU) 2016/161. Any batch number applied to the primary packaging components (e.g. blister strips, bottle labels, etc.) during the repackaging operation should be the same as that applied to the outer carton of the repackaged/relabelled product.
Chapter 7 describes that a written Contract between the Contract Giver and the Contract Acceptor must be established and where the marketing authorization holder (MAH) and the manufacturer are not the same, appropriate arrangements should be in place, taking into account the principles described in chapter 7. Are direct agreement a requirement between the MAH, MIA holder responsible for QP certification and sites involved in the various stages of manufacture, importation, testing and storage of a batch before it undergoes certification?
A direct written contract should be in place between MAH and the MIA holder responsible for QP certification of the product.
A direct written contract should also be in place between the MIA holder responsible for QP certification of the product and sites involved in the various stages of manufacture, importation, testing and storage of a batch before it undergoes certification (hereafter: contract manufacturers). It is also acceptable to have a direct written contract between multiple parties, such as MAH and MIA holder responsible for QP certification of the product and contract manufacturers or any other entities included in the manufacturing/supply chain, provided that relevant activities and responsibilities for each entity are clearly defined.
A “chain of contract” setup may exceptionally be acceptable instead of direct written contracts as detailed above, provided the following principles are adhered to:
Regardless of the contract setup used, it must be ensured that all relevant activities and responsibilities for each entity are clearly defined and that the contract setup complies with any additional requirements of the national legislation.
The following terminology are used throughout this document:
Written contract: A contract accordance to the requirements of EU GMP chapter 7. The word Technical agreement as used in EU GMP annex 16 are in this context considered identical to a written contract
Direct written contract: Contract signed between the parties, that actually perform the activities stated in the contract, e.g. the MIA holder responsible for QP certification as a contract giver and the contract manufacturer as a contract acceptor or the MAH as a contract giver and the MIA holder responsible for QP certification as a contract acceptor.
“Chain of contract” setup: A setup where one or more parties (sites/companies) are acting as signatory in a chain of contracts that links them together. Thus, the setup introduces one or several separate legal entities between the contract giver - e.g. a MIA holder responsible for QP certification and the contract manufacturer as a contract acceptor. In fact, the GMP activities concerned are sub-contracted over one or several levels.
Suspected product quality defects (e.g. product deterioration, packaging mix-up, among others) should be reported to the competent authority with responsibility for the manufacturing site (or importer where the manufacturer is located outside the EEA), and to the competent authority in each EEA market supplied. In case of impact to EU centrally authorised products, the EMA must also be notified. This notification should be prior to taking any market action, unless, as per paragraph 8.26 of Chapter 8, the need for market action is so serious as to warrant immediate action to protect patient or animal health.
Confirmation of a quality defect does not require completion of the investigation. Reporting should be initiated when available information supports the detection of the issue and when the initial assessment of the potential risks presented to patients/animals indicates that it could result in market action. Notification to competent authorities should typically take place within one working day of confirmation that reporting is required.
In cases where a suspected quality defect involves multiple manufacturing sites, reporting responsibilities should be defined in a technical agreement. It is normal expectation that the MAH and site of final EU batch certification should take the lead on reporting, unless otherwise justified.
Manufacturers are encouraged to notify their national competent authority (or EU Supervisory Authority for sites located outside the EEA) of confirmed serious GMP issues with the potential to lead to a suspected product defect requiring market action (e.g. media fill failure, serious equipment failure, etc.). Confirmation of a serious GMP issue does not require completion of the investigation; reporting should be initiated when available information confirms the detection of the issue.
Serious GMP issues which may result in an abnormal restriction in supply should be notified to the MAH and relevant competent authorities in accordance with legal obligations given in Art 23(2) of Directive 2001/83/EC, Art 27 of Directive 2001/82/EC, Regulation 726/2004 and EMA guidance1:
In the event that a medicinal product which is the subject of a marketing authorisation issued by an EEA authority, and which is marketed in another third country (or countries) then the marketing authorisation holder shall forthwith inform the relevant EU competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned (e.g recalls or serious GMP issues). This is even if the particular batch subject to the prohibition or restriction is not marketed in the EEA.
In cases where national competent authorities set additional national expectations regarding what quality defects should be reported and the timelines for reporting, these should be complied with.
A batch recall is defined in the Compilation of Community Procedures as "The action of withdrawing a batch from the distribution chain and users. A batch recall may be partial, in that the batch is only withdrawn from selected distributors or users". This definition covers the entire distribution chain from all points following manufacture through to the end user, the patient. Also, it is possible that the MAH or its subsidiaries are actors in the supply chain, acting as the distributor in certain cases. In such cases, the MAH or its subsidiaries should be regarded as also being part of the distribution chain.
A batch of medicinal product is considered to have been 'placed on the market' when one of the following takes place:
National competent authorities should be notified of all recall action proposed after the product has been placed on the market. In situations where the MAH can demonstrate that the batch is reconciled without issuing a recall notice, the national competent authority may agree that public recall communication throughout the distribution network is not necessary.
It is acknowledged that certain short expiry products (e.g. radiopharmaceuticals, advanced therapy medicinal products, etc.) may be shipped under quarantine prior to certification. Retrieval of batches during this quarantine period may be managed within the pharmaceutical quality system.
Directive 2001/83/EC as amended (Directive 2001/82/EC for veterinary medicinal products) states that manufacturing-authorisation holders are obliged to use, as starting materials, only active substances that have been manufactured in accordance with the detailed guidelines on GMP for starting materials. Thus the legislation puts the responsibility on the manufacturing-authorisation holders using the active substance and does not foresee mandatory routine inspections of active-substance manufacturers.
To provide guidance on how GMP compliance of active-substance manufacturers should be established, guidance documents have been published on this website, including the 'guidance on the occasions when it is appropriate for competent authorities to conduct inspections at the premises of manufacturers of active substances used as starting materials' as part of the Community procedures. This document states that it is expected that manufacturing-authorisation holders will normally gain assurance that the active substances it uses are manufactured in accordance with GMP through audit of the active-substance suppliers.
In addition, a number of questions and answers on audits of active-substance manufacturers on this page provide further guidance.
Manufacturing-authorisation holders sometimes confuse the role of inspectorates with their own obligations but nevertheless, when inspection reports or GMP certificates issued by European Economic Area (EEA) mutual-recognition-agreement (MRA) partners or other recognised authorities are available, these can provide useful information to manufacturing-authorisation holders.
However, these alone cannot fulfil the statutory obligations of the manufacturing-authorisation holder or the requirements of section 5.29 of the GMP guideline, but the results of inspections may be used together with other supporting information in a risk-based approach by the manufacturer in establishing priorities for its own audit programme of active-substance suppliers.
The document 'guidance on the occasions when it is appropriate for competent authorities to conduct inspections at the premises of manufacturers of active substances used as starting materials', published as part of the Union procedures, states that it is expected that manufacturing-authorisation holders will gain assurance that the active substances they use are manufactured in accordance with GMP through audit of the active-substance suppliers. Article 46 (f) of Directive 2001/83/EC states: "The holder of the manufacturing authorisation shall verify such compliance either by himself or, without prejudice to his responsibility as provided for in this Directive, through an entity acting on his behalf under a contract". Manufacturers may not have the necessary expertise or resources to conduct their own audits and therefore may contract with third parties to undertake relevant audits. MIA holders may rely on audits carried out by active substance manufacturers on their suppliers of active substance intermediates provided that there is an appropriate contractual arrangement in place between the MIA holder and the manufacturer of the active substance.
Section 5.27 of the GMP guideline requires that the selection, qualification, approval and maintenance of suppliers of starting materials, together with their purchase and acceptance, are performed by staff that have a current knowledge of the suppliers, the supply chain and the associated risks involved.
An audit conducted by the manufacturing-authorisation holder itself should be integral to the manufacturer's quality-assurance system and subject to the basic GMP requirements, i.e. conducted by properly qualified and trained staff, in accordance with approved procedures. It should be properly documented. These aspects can be inspected as necessary by the competent authorities.
If a third party is involved, the arrangements should be subject to chapter 7 of the GMP guideline. There should be evidence that the contract-giver has evaluated the contract-acceptor with respect to the aspects described above.
All parties involved should be aware that audit reports and other documentation relating to the audit will be made available for inspection by the competent authorities if requested. This should normally provide sufficient assurance that the results of an audit carried out by the third party are credible, thus waiving the need for an audit conducted by the manufacturing-authorisation holder itself. A third-party contractual arrangement may lead to a conflict of interest arising on the part of one or more of the parties involved. Conflicts of Interest should be regarded as any influencing factor that may affect the judgement of the auditor resulting in an audit report that may not provide a full and impartial assessment against EU GMP requirements.
Therefore, the MIA holder should ensure that there are arrangements in place to assure that any conflicts of interests are declared, and where declared, that they are assessed for their impact on the impartiality of the audit.
Potential conflicts of interest may arise from diverse sources and may include for example:
Definition of API starting materials, and hence which steps to perform under GMP, is a critical aspect where conflicts of interest may arise, especially in cases where an API intermediate is manufactured at a site different from the final API manufacturing site.
In addition to the arrangements to assure that conflicts of interest are declared, each auditing body should have a quality system that supports the quality and integrity of audits.
Where a conflict of interest has been declared by a third-party auditor or contracting company, they should document the nature of the conflict of interest, the impact it may have on the conduction of the audit and how the overall assessment of the GMP compliance status of the auditee is assured.
This topic should be addressed in the technical contractual arrangements. Any measures taken by the contract-giver should be documented, e.g. signed undertakings by the auditors. The absence or presence of conflicts of interest on the part of auditors or contracting parties should be identified.
QPs should ensure that the written final assessment and approval of third-party audit reports includes an evaluation of a declaration or absence of any conflicts of interest made by auditors and/or the contracting parties.
Conflicts of interest may come to light after the QP has relied upon a third-party audit report and it may be necessary for the QP to undertake a retrospective assessment.
The principles outlined above could be used in case of joint audits between different manufacturing authorisation holders or in those cases where the drug manufacturers have jointly contracted the third party auditor and have signed the contract before the audit took place, using the same active substance supplier, provided that the scope of the audits can be shown to be applicable to the active substances of mutual interest.
The EEA inspectorates are not generally in favour of 'paper-based audits' per se as they do not provide the same level of assurance as on-site assessments, but do accept that they have a part to play in a risk-based strategy.
They may be particularly applicable when recent positive inspection information is available and where satisfactory audits have been concluded in the past. They cannot replace on-site audits of active-substance suppliers but can be a useful interim and temporary measure within the manufacturer's audit programme.
Importers are manufacturing-authorisation holders and so the obligations under Article 46f/50f of Directive 2001/83(2) apply to them. For importers, the possibility of a second-party audit performed by the third-country manufacturer that uses the active substance as a starting material may be a further option.
Importers are already obliged to ensure that the third-country manufacturer complies with standards of GMP equivalent to those of the European Community and should have established arrangements in line with chapter 7 of the GMP guideline. They should therefore be fully satisfied that the third-country manufacturer has adequately demonstrated that the active substances it uses for products destined for the European Community have been manufactured in accordance with GMP.
Importers may of course choose to verify the standards of GMP at the active-substance suppliers themselves or through a third party. Whichever option is chosen, the questions and answers above are also relevant.
First, the responsibility for only using active substances that have been manufactured in accordance with GMPs is placed on the holders of a manufacturing authorisation (MA). An inspection of the active substance manufacturer by an EEA authority does not liberate a MA holder from this responsibility.
Article 111 (1f) of Directive 2001/83/EC and Article 80(1) of Directive 2001/82/EC, have provision for the competent authority of the Member State concerned to carry out inspections of starting material manufacturers at the specific request of the manufacturer. The request for the inspection should be made to the EEA competent authority where the site is located or, in case of sites located in third countries, to a competent authority where the starting material is used in the manufacture of medicinal products. If this is not the case, any EEA authority can be approached.
There is no guarantee that such a request will be fulfilled since competent authorities primarily use risk-based principles to plan starting material inspections. Thus, when a starting material manufacturer applies for a voluntary inspection, this does not constitute an obligation for the competent authority to trigger an inspection.
The notice to applicants requires the submission of a declaration signed by the qualified person (QP) that the active substance used is manufactured in accordance with GMP. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration? H+V September 2008
Full compliance with GMP for finished products and active substances is a legal obligation for manufacturing-authorisation holders. It is recognised that for a small number of medicinal products, the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business.
Alternative sources should normally be sought, but in exceptional cases the manufacturing-authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation.
The declaration provided by the QP should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. The European Medicines Agency will collect experience with this approach, which can be used as a basis for discussion on related amendments to guidelines in the future.
Inspectors may need to see audit reports during inspections as part of the assessment of the manufacturing-authorisation holder's systems for confirming GMP compliance of active substance manufacturers or suppliers. Inspectors will expect to see the full details of these reports upon request, including responses received from the audited site, indication of closure of deficiencies raised or commitments made.
The QP has the ultimate responsibility to ensure that audit reports are properly evaluated when the audit is performed by a third party. The written final assessment document should provide a comprehensible summary of this evaluation and should be readily available and shared with authorities, if requested.
The assessment should include all expected elements of the auditing process and audit report(s) identified before, during and after the audit. In particular, this includes verification of contractual arrangements, scope and appropriate duration of audit, adequate competence of auditors considering the scope of the audit, planned audit frequency, and CAPAs whether adequate and how these are to be followed up. Any conflicts of interest identified should be discussed.
As a minimum, the following is expected to be included in the report:
There should be a clear record of the products, the stages of manufacture and the buildings audited. If access was denied to any relevant areas of the site this should be recorded and explained. The list should clarify which of the active substances in the scope of the audit are manufactured in multi-purpose equipment or buildings as either final product or any of the intermediate stages.
Auditors should have sufficient scientific, technical and other experience to enable them to perform an adequate and thorough audit of the active substance manufacturer, as related to the planned scope of the audit. Where a proposed auditor lacks an appropriate level of direct experience in the field of active substance manufacture, he or she should undergo a documented training and assessment programme in the areas that are relevant to the audit, taking into account the auditor's anticipated role in the audit and the technologies that are likely to be encountered during the audit. Auditors must also be trained and assessed in their knowledge and understanding of EU GMP part II and in auditing techniques in general. The training and assessment should be fully documented.
The qualification and experience of contracted auditors are the same as the requirements for the manufacturing-authorisation holder's own auditors.
Article 111 (1b) of Directive 2001/83/EC requires that Member States have a system of supervision including inspections at an appropriate frequency based on risk, at the premises of the manufacturers, importers, or distributors of active substances located on its territory.
In line with the document “Model for Risk Based Planning for Inspections of Pharmaceutical Manufacturers” available in the Compilation of Union Procedures, sterile and biological active substances are considered a relatively higher risk. Consequently, competent authorities may decide to submit these substances to a higher or a set inspection frequency.
The Q&As on Quality Part 1, address the exceptions where the formulation of an active substance can be described under CTD section 3.2.S.
For the manufacture of biological active substances, Part II and Annex 2 of the GMP guidelines apply. While quality risk management principles also apply to the formulation of a biological active substance, some aspects of GMP part 1 as described below are more appropriate and are expected as a minimum:
The sampling of excipients used for the formulated active substance should comply with GMP Annex 8 and retention samples of excipients should be kept under the responsibility of the medicinal product manufacturer (in accordance with GMP Part I., 1.9 (viii) and GMP Annex 19).
Excipients used by the manufacturer of the formulated active substance should be included in the Periodic Quality Review (in accordance with GMP Part I., 1.10 (i)).
Directives 2001/82/EC and 2001/83/EC, as amended, include obligations for manufacturing-authorisation holders only to use active substances that have been manufactured in accordance with GMP. Provision is also made for inspections of active-substance manufacturers but only under certain specified circumstances.
IMPs are unaffected because the obligations of manufacturing-authorisation holders in this case are laid down in Directive 2005/28/EC, which does not contain corresponding requirements for active substances. Furthermore, this is made clear in the introduction to part II of the GMP guideline.
Part II of the GMP guideline does include a short section on new active substances to be used as starting materials for IMPs and these remain as recommendations with no mandatory force. Nevertheless, active substances used in the manufacture of marketed products are already required to comply with GMP irrespective as to whether they may also used in the manufacture of IMPs.
The sampling plan for sterility testing should take account of the definition of a batch as stated in the glossary of the GMP guideline together with the recommendations of the new annex 1 section 10.6, each steriliser load is considered to be an independent sub-batch. Consequently, one sterility test should be performed per sub-batch. The number of samples per steriliser load should conform to European Pharmacopoeia requirements, section 2.6.1.3.
However, Section 8.54 of the new annex 1 and Annex 17 allow the introduction of parametric release to replace sterility testing thus waiving the sampling requirements. A variation to relevant existing marketing authorizations would be necessary.
This introduction implies consideration for the bioburden assay before sterilisation to be performed per batch (annex 1 section 10.4 and annex 17 section 4.9). Consideration should also be given to the “Real Time Release Testing guideline” ref EMA/CHMP/QWP/811210/2009-Rev1 and guideline-sterilisation-medicinal-product and active-substance ref EMA/CHMP/CVMP/QWP/850374/2015
For large-volume parenteral where the sterilisation cycle has been qualified with an overkill level, and in exceptional situation such as insufficient historical data regarding sterility testing to support parametric release, the regulated user can follow an alternative sampling plan in accordance with a specific internal procedure agreed with the supervisory authority (unless already specified in the marketing authorisation).
This procedure should state the need to sample from each steriliser load including the coolest location identified during the steriliser qualification. The number of samples per load should be defined based on a risk-based approach and the overall number of samples per batch should conform to European Pharmacopoeia requirements, section 2.6.1.3.
Update January 2019: This Q&A has been superseded by the Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container. Please refer to this guideline for further information.
The specification limits for bioburden should be NMT 10 CFU/100 ml, in line with the guideline “sterilisation-medicinal-product and active-substance ref EMA/CHMP/CVMP/QWP/850374/2015)".
Note for guidance on manufacture of the finished dosage form - First version and Note for guidance: Manufacture of the finished dosage form).
When a prefilter is installed, unless otherwise justified, a bioburden limit of 10 CFUs/100 ml before first filtration is achievable in principle and is strongly recommended from a GMP point of view. Higher bioburden limits should not be justified by the high capacity of two consecutive bacteria retaining filters.
However, when appropriate justification is submitted (processes involving fermentation or other biological or herbal components, use of purified water for ophthalmic preparations, etc.), a bioburden limit of higher than 10 CFUs/100 ml before prefiltration may be acceptable. In such cases, it should be demonstrated that the first filter has the capability to achieve a bioburden prior to the last filtration of NMT 10 CFUs/100 ml, in line with the notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).
Rapid method is one of the alternative monitoring systems that may expedite the detection of microorganisms pending that the requirements of annex 1 points 9.28, 9.30 and 9.31) are fulfilled.
Annex 1 distinguishes two types of isolators:
An isolator designed to interface with material transfer airlock that uses a reproducible bio-decontamination steps (active vapor-phase hydrogen peroxide (VPHP) decontamination) might be considered as a closed isolator as per Annex 1 glossary definition, provided that the interface can be shown to constitute an efficient barrier to the surrounding environment based on documented evidence from qualification/validation studies and monitoring data.
For instance. This might be possible , as long as the VPHP cycles are validated and filling chamber environment is protected by the sealed door (as barrier) while the integrity of airlock is broken during loading followed by decontamination cycle before opening the barrier again. Requirements of Annex 1 points 4.10, 4.11 and 4.12 should be considered.
It needs to be pointed out, that these elements should be discussed with the respective supervisory authority.
Annex 1 point 10.4 states that for products authorised for parametric release, a supporting pre-sterilisation bioburden monitoring programme for the filled product prior to initiating the sterilisation cycle should be developed and the bioburden assay should be performed for each batch (sub batch) The sampling locations of filled units before sterilisation should be based on a worst case scenario and be representative of the batch. Any organisms found during bioburden testing should be identified and their impact on the effectiveness of the sterilising process determined. Where appropriate, the level of endotoxin/pyrogen should be monitored.
Annex 17 point 4.9 states that a pre-sterilization bio-burden monitoring program for the product and components should be developed to support parametric release. The bioburden should be performed for each batch. The sampling locations of filled units before sterilization should be based on a worst-case scenario and be representative of the batch. Any organisms found during bioburden testing should be identified to confirm that they are not spore forming which may be more resistant to the sterilizing process
The company should consider the bioburden by the batch or sub-batch to be sterilized.
A specific consideration should be given to the time between sampling, sterilisation and testing.
Any alternative to this approach should be thoroughly justified and should consider:
Traceability is the ability to retrieve the history of the manufacturing and distribution operations of a batch of a medicinal product.
The data recorded through the traceability system should allow efficient investigation in case an incident occurs and should allow recalls of (potentially) defective products.
In the case of packaged medicinal gases, the packaging components (shells and valves) are reusable. It is therefore necessary to record additional information, in particular in relation to the use and maintenance of these components.
The cylinder is the combination of the shell and its valve.
For safety reasons, shells are individually identified (specific reference). Individual traceability is therefore possible. The date of the last hydrostatic pressure test (or equivalent test) should be recorded.
Shells may be fitted with simple valves (e.g. pin-index valves) or integrated valves. Integrated valves are individually identified (individual identification reference). Individual traceability is therefore possible. This is not the case for simple valves, which mostly have only a serial number corresponding to a group of valves.
The design of integrated valves, which are medical devices, is complex. These valves are also subject to periodic preventive maintenance operations. In terms of risk, more serious incidents have been reported with cylinders having this type of valve.
Therefore:
Each shell-and-valve combination should be traceable.
The manufacturing batch records should include the individual identification references of the cylinders of each batch of finished product (see EU GMP guideline annex 6, section 17, (g) and (m)).
The distribution records should include the individual identification references of the cylinders delivered to each customer.
In practice, depending on the scale of operation, it may be difficult to ensure effective traceability without a computerised system. Use of bar codes or electronic chips on the cylinders may facilitate this. Any computerised system used to ensure traceability should conform to the requirements of annex 11 of the EU GMP guideline.
Should a manufacturer of a medicinal gas receive a serious complaint relating to the quality of the medicinal gas itself or the packaging components, the system in place should allow the identification of the affected cylinders and, where necessary, the recall of any affected cylinders from the market.
A defect relating to packaging components may require identification of specific cylinders within a finished product batch or identification of cylinders present in a number of finished product batches in order to establish the extent of any recall required.
For example, an effective traceability system should allow effective recalls of cylinders fitted with defective valves based on:
Diethylene Glycol (DEG) and Ethylene Glycol (EG) have been implicated in at least 30 incidents of excipients contamination, particularly glycerol and propylene glycol, in the last 90 years, resulting in mortality and serious morbidity in patients, especially in the paediatric population, receiving contaminated medicinal products.
The first incident resulting in the death of 107 people in the United States, following ingestion of sulphanilamide elixir containing diethylene glycol was reported back in 1937. Between 1937 and 2021, there have been diethylene glycol-related poisonings in India, China, Panama, Haiti, Bangladesh, Argentina, and Nigeria.
More recently, in 2022 and 2023, the World Health Organization published a series of Medical Product Alerts identifying medicinal products, mostly paediatric formulations, that were contaminated with DEG and EG. Several countries were affected by the contaminated products including Gambia, Indonesia, Uzbekistan, Cambodia, Marshall Islands, Micronesia, Cameroon, and Iraq. The most prominent incident refers to the death of a high number of children in Gambia and Indonesia receiving contaminated syrup formulations.
Such incidents are related to both accidental cross-contamination of glycerol or propylene glycol with industrial grade materials and, in some cases, to intentional substitution. Although the most recent cases of contamination are still under investigation, historical data suggests that:
EU GMP, and specifically Chapter 5 on supplier qualification and monitoring, requires all manufacturing companies to confirm that all its raw materials are checked on receipt to confirm their identity and quality. Competent authorities expect product manufacturers to routinely ensure that incoming samples of glycerol, propylene glycol, and macrogols (polyethylene glycol) with a relative molecular mass below 1000, are tested according to the relevant European Pharmacopoeia monograph.
The European Pharmacopoeia monographs for glycerol [0496, 0497], propylene glycol [0430], and macrogols [1444] (polyethylene glycol) with a relative molecular mass below 1000 include a specific limit test for ethylene glycol/diethylene glycol.
It is correct that annex 8 does provide for a relaxation of identity testing of every container, but it also states that this would not normally be possible if brokers or intermediates were involved in the chain of supply. Therefore, according to Annex 8, sampling of only a portion of containers would not normally be possible.
Glycerol, propylene glycol, and macrogols (polyethylene glycol) with a relative molecular mass below 1000, are commercial articles that are widely used in the food and other industries. Generally speaking, the supply chain for glycerol and other excipients tends to be complex and lengthy. The involvement of brokers is common in the supply chain.
When designing supplier-assurance and incoming-goods-control programmes, companies should consider glycerol, propylene glycol and macrogols (polyethylene glycol) with a relative molecular mass below 1000, as higher-risk materials.
Manufacturers, especially importers, should be able to exhibit a good knowledge of the supply chains and apply this knowledge and principles of quality risk management to their programmes for supply-chain management, in line with Annex 16 point 1.7.2. Inspectors will look to ensure that the manufacturer’s basis for qualification of the supply chain is demonstrably robust for higher-risk materials, such as glycerol, propylene glycol and macrogols (polyethylene glycol) with a relative molecular mass below 1000. Unless scientifically justified (as described in Q3 above), identity testing of starting materials and the European Pharmacopoeia limit test for DEG/EG will be performed on each container.
This point is acknowledged and alternative tests are under consideration. The European Pharmacopoeia DEG/EG limit test remains the official method for confirmation of compliance with the monograph.
In application dossiers for new marketing authorisations (MAs), or in case of relevant variations for existing MAs (for example, replacement of an excipient) for medicinal products containing excipients at high-risk of DEG/EG contamination (e.g., glycerol, propylene glycol and certain grades of macrogols (polyethylene glycol)), excipient specifications should ensure that the risks from potential DEG/EG contamination are mitigated, i.e., a specification for DEG/EG content is included. Suitable test methods are included in the European Pharmacopoeia monographs for glycerol [0496, 0497], propylene glycol [0430], and macrogols [1444]. The mitigation should be discussed and evaluated in the context of the overall control strategy for the finished product.
Sufficient information regarding satisfactory control of this risk will be required in the dossier before approval of the MA application or variation.
For existing approved medicinal products, no variation application is required, except for those few specific types of variations referred to in the first paragraph. However, as a minimum, the specific European Pharmacopoeia control for DEG/EG should be conducted along with the identity test at receipt of each batch of the high-risk excipients above-mentioned. The excipients are required to comply with the current European Pharmacopoeia monograph, and as the specification approved in the dossier will have been that of the European Pharmacopoeia, the risk of DEG/EG contamination will have been appropriately controlled. Compliance with this requirement can be verified during GMP inspections.
Where a company manufactures products for external use, and when it has justified that the presence of DEG/EG in these products poses a low risk, the omission of the test for DEG/EG on each container may be accepted by the supervisory authority.
Annex 8 of the GMP guideline states that the identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labeled. However, the annex goes on to say that it is improbable that a procedure could be satisfactorily validated for starting materials for use in parenteral products.
Unless variations are submitted for all affected products, the registered method for confirming identity should be performed. However, there is no restriction on the performance of additional testing and the use of NIR to confirm container-wise confirmation of identity can provide useful information. Under these circumstances, the requirements of the marketing authorisation will be deemed to have been met by carrying out the registered method for confirmation of identity on a statistically representative composite sample when this is supplemented with NIR analysis of every container.
The NIR method should be validated in line with the recommendations of the guideline on the use of near infrared spectroscopy by the pharmaceutical industry and the data requirements for new submissions and variations.
Templates of spreadsheets help to avoid erroneous calculations from data remaining from previous calculations. They should be suitably checked for accuracy and reliability (annex 11 p7.1). They should be stored in a manner which ensures appropriate version control (chapter 4 p4.1).
Data integrity should be ensured by suitably implemented and risk-assessed controls. The calculations and the files should be secured in such a way that formulations are not accidentally overwritten. Accidental input of an inappropriate data type should be prevented or result in an error message (e.g. text in a numeric field or a decimal format into an integer field). So-called 'boundary checks' are encouraged.
Validation according to paragraph 4 of annex 11 is required at least for spreadsheets that contain custom code (e.g. Visual Basic for applications). Formulas or other types of algorithm should be verified for correctness.
Data security includes integrity, reliability and availability of data. During validation of a database-based or inclusive system, consideration should be given to:
Risk management should be applied throughout the whole life-cycle. A first risk assessment should be performed to determine the GMP criticality of the system, i.e. does the system have an impact on patient safety, product quality or data integrity? User-requirement specifications are usually developed with consideration of potential risks and form the basis for the first formal risk assessment.
Complex systems should be evaluated in further more detailed risk assessments to determine critical functions. This will help ensure that validation activities cover all critical functions.
Risk management includes the implementation of appropriate controls and their verification.
The way to check whether a computerised system is fit for its intended purpose is to define user requirements and perform a gap analysis to determine the validation effort for retrospective validation. These user requirements should be verified.
Computerised systems should be reviewed periodically to confirm that they remain in a validated state. Periodic evaluation should include, where applicable, the current range of functionality, deviation records, change records, upgrade history, performance, reliability and security. The time period for revaluation and revalidation should be based on the criticality of the system.
The requirements for storage of electronically data and documents do not differ from paper documents. It should be ensured that electronic signatures applied to electronic records are valid for the entire storage period for documents.
Small devices are usually off-the-shelf pieces of equipment that is widely used. In these cases, the development life-cycle is mainly controlled by the vendor. The pharmaceutical customer should therefore reasonably assess the vendor's capability of developing software according to common standards of quality.
A vendor assessment needs to be performed and the application needs to be verified against the requirements for the intended use. From the perspective of the regulated industry, the implementation of such a device is driven by an implementation life-cycle. At minimum the following items need to be addressed:
Small manufacturing devices are sometimes only equipped with microprocessors and firmware and are not capable of high-level administration functions. Moreover, data is often transient in nature in these devices. Due to the latter there is no risk of inadvertently modifying data. An audit trail is therefore not necessary and user access may be limited to those functions of parameter control.
As long as this functionality is not supported by the supplier, it may be acceptable to describe in a procedure the fact that a print-out of the related audit trail report must be generated and linked manually to the record supporting batch release.
Commission Directive 2001/20/EC defines an IMP as 'a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.'
An active substance would be considered an IMP if presented in a packaged form for use in a clinical trial. Any such packaging operation could only be carried out by a site holding an IMP manufacturing authorisation.
Any form of mixing or processing the active substance with other substances would also result in the need for a manufacturing authorisation for IMPs if the resulting product is to be used in a clinical trial.
Physical processing such as milling of an active pharmaceutical ingredient would not constitute IMP manufacturing.
The above does not refer to reconstitution. Separate guidance on this subject is under development.
The QP of a site that is manufacturing a drug product intermediate should assure that the product is produced and controlled in compliance with the EU GMP guideline, in particular the requirements of annex 13.
A product specification file should be developed with contributions from the QPs and other technical personnel of the sites involved with the other manufacturing activities of the IMP. The sponsor of the clinical trial should also be involved in this process. While this may be in a rudimentary form and contain little detail, it should be developed as knowledge of the product evolves and include specifications for critical parameters and controls. The product specification file should be updated and evolve in line with the product development as envisaged in annex 13.
The development of the product specification file should be managed under a technical agreement or a number of technical agreements between the various manufacturing sites. These should include the QP responsible for the final certification of the product and the sponsor, if the sponsor has already been appointed. In any event, final release of the product to trial sites should take place only when the sponsor has established that the product has been manufactured in compliance with the terms of the approved clinical-trial application (as required by annex 13.44). This is defined in annexes 13.40 and 13.44: 'The sponsor should ensure that the elements taken into account by the QP when certifying are consistent with the information notified pursuant to Article 9(2) of Directive 2001/20/EC.'
This is normally possible only if a manufacturing authorisation has been granted to the site by the national competent authority.
According to Article 9(1) of Directive 2005/28/EC, the “authorisation, as provided for in Article 13(1) of Directive 2001/20/EC, shall be required for both total and partial manufacture of IMPs, and for the various processes of dividing up, packaging or presentation.”
However, an exemption to this obligation is foreseen in Article 9(2) of Directive 2005/28/EC: 'Authorisation, as provided for in Article 13(1) of Directive 2001/20/EC, shall not be required for reconstitution prior to use or packaging, where those processes are carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member States to carry out such processes and if the IMPs are intended to be used exclusively in those institutions.' In addition, reference should be made to section 33 of annex 13 in respect of any re-labelling to extend shelf life.
The sponsor has the ultimate responsibility for all trial activities performed at the investigator site, but should seek the advice of the QP of the IMP manufacturer, if possible, or the clinical-trials pharmacist at the investigator site regarding:
The sponsor should exercise control over the entire chain of distribution of IMPs, from manufacture or importation into the EEA, through to supply to the investigator sites, so as to guarantee that IMPs are stored, transported, and handled in a suitable manner.
When an IMP originates from a third country, the importer is responsible for verifying that the transportation and storage conditions for the product are suitable. For products originating within the EEA, the manufacturer is responsible for transportation and storage conditions. The respective responsibilities of the sponsor, manufacturer, importer and, where used, distributor should be defined in a technical agreement.
Storage conditions during transportation should be validated or monitored using a suitable temperature-measuring device that is capable of showing fluctuations in temperature e.g. Temperature Logger. The choice of method of transport should be influenced by the nature and sensitivity of the product and should ensure timely delivery of IMPs to the investigator sites.
The outer packaging should be labelled showing the final destination, the name of manufacturer or sponsor and the storage conditions required.
IMPs should be packaged to prevent contamination and unacceptable deterioration during storage. The sponsor should determine acceptable storage temperatures and any other required storage conditions for the IMPs (e.g. protection from light).
The sponsor should ensure that all involved parties (e.g. monitors, investigators, pharmacists, storage managers) are aware of these conditions and the actions to be taken in the event that the conditions are not met.
Where appropriate, there should be a restricted area for the storage of IMPs. The temperature of the areas and equipment used for the storage should be monitored using suitable means, such as a temperature recorder or, as a minimum, a record of the maximum and minimum temperatures, at a suitable frequency (for example, daily).
The sponsor should ensure that written procedures include instructions that the investigator or institution should follow for the handling and storage of IMPs. The procedures should address adequate and safe receipt, handling, storage, where relevant any reconstitution process to be carried out before administration, retrieval of unused product from subjects, and return of unused IMPs to the sponsor (or alternative disposal, if authorised by the sponsor and in compliance with the applicable regulatory requirements).
Procedures should also give instructions on the actions to be taken when defined conditions are not met.
The sponsor should ensure that the documents listed in chapter 8, 'essential documents for the conduct of a clinical trial' of the guideline for good clinical practice are maintained and accessible to those parties authorised to review them.
Yes. Annex 14 applies to medicinal products derived from human blood or plasma, fractionated in or imported into the EEA. It applies to both the drug substance and the drug product manufacturing. In the case of plasma for fractionation, Directive 2003/63/EC (which introduced the central PMF) lists human plasma as “starting material”. Therefore, by definition, plasma for fractionation is not considered to be drug substance/API, but “starting material”. Drug substance is the purified API/active substance in bulk form (e.g. Factor VIII purified via fractionation out of the starting material), and drug product is the medicinal product in its final dosage form. EU-GMP Part II includes active substances that are produced using blood or plasma as raw materials.
Yes. The extraction of active substances from human blood or plasma is the first step in the manufacture of the active substance which will be used in a medicinal product derived from human blood or plasma. There may be differences in how manufacture of this type of active substance is regulated in different Member States with some countries requiring that the manufacturer holds a manufacturing authorization (under Article 40 of Directive 2001/83/EC) whilst others may require registration as an active substance manufacturer (under Article 52a of Directive 2001/83/EC). As such, in the EEA this activity needs to take place at a manufacturing site that is authorized or registered for that activity and in accordance with the relevant GMP guidelines, (Part I or Part II as appropriate, and GMP Annex 14. Likewise for manufacturing sites located outside the EEA, GMP guidelines need to be complied with.
GMP Annex 14 states that the QP of the manufacturing site has the following responsibilities (2.5, 3.3, 4.2, 6.8, 8.2-3):
It is recognized that only sites that are authorized for manufacturing medicinal products (MIA holders) are obliged to have a QP and that other manufacturing sites, like sites registered for manufacturing of APIs and sites outside the EEA, do not have that obligation.
Annex 14, paragraph 2.5 allows that subsequent steps after collection (including the freezing of plasma) and testing of plasma take place in a blood establishment under the responsibility of their responsible person. To address this particular situation and to ensure the legal responsibilities of the QP who is certifying the batch of finished product are properly addressed, the fractionation plant/manufacturer should establish a contract, in accordance with Chapter 7 of the GMP Guide, with the blood establishment that defines respective duties and details the requirements in order to ensure compliance. The responsibility stays with the QP of the finished product manufacturer. Likewise, in case of manufacture of APIs derived from human blood or plasma, the API manufacturer’s person responsible for release as specified in GMP Part II paragraph 2.14, should be involved in drawing up a technical agreement specifying the respective duties of each party such that the legal responsibilities of the QP performing certification of the batch are fulfilled.
EU legislation requires a manufacturer to have at least one QP at its disposal but a site may have more than one QP who may certify batches on behalf of the manufacturer.
Annex 16 of the EU GMP guideline gives guidance in relation to situations where different stages of manufacture of a batch take place at different manufacturing sites.
In such cases, the overall responsibility for correct manufacture of the batch lies with the QP performing final certification of the batch before release for sale. It is also possible that, at a single manufacturing site, different QPs could be responsible for certification of different stages of manufacture of the batch. However, as before, the QP performing final certification before release holds overall responsibility for manufacture of the batch in accordance with GMP and the marketing authorisation.
In order to satisfy the criteria in Annex 16 section 3 for handling unexpected deviations, all registered specifications for active substances, excipients, packaging materials and medicinal products must be met.
Registered specifications for medicinal products include in-process, bulk and finished product specifications which have been included in the MA application.
The criticality of registered in-process specifications may vary depending on the quality attribute tested, the impact to subsequent manufacturing processes and ability to test the quality attribute in the finished product. It may therefore be possible to accept deviation from an in-process specification where risk assessment confirms that there is no impact to manufacturing process or product quality.
Non-compliance with registered specifications (except where excursions from in-process specifications can be accepted based on quality risk management principles) therefore fall outside the scope of Annex 16 section 3, and the QP would not be able to certify the affected batches under the Annex 16 provisions for handling unexpected deviations.
What is an 'unexpected' deviation?
The process itself should be designed to comply with the registered requirements (fit for purpose). A deviation can be considered as 'unexpected' until the time of discovery. Where the relevant authorities have confirmed the need to avoid supply disruption, repeat deviations thereafter are no longer 'unexpected' but may be considered for QP certification and accepted while corrective and preventive action is in progress and where the provisions of Annex 16 paragraph 3.1 are met.
Planned deviations or deviations that are caused by incorrect communication between marketing authorisation holder (MAH) and manufacturers (e.g. if the MAH fails to notify the manufacturer of relevant changes to the MA) are outside the scope of the paragraph 3.1. The marketing authorisation holder should submit an application for a variation to the marketing authorisation, if needed.
Does Annex 16 permit QP certification of more than one batch affected by the same unexpected deviation?
If more than one batch has already been manufactured and/or tested at the time of discovery of the unexpected deviation, then it is acceptable to consider QP certification of all these batches under the provisions of Annex 16 section 3.
Following discovery, repeated deviations from the manufacturing process and/or analytical control methods should be considered changes, and variations to the affected marketing authorisations must be submitted. In exceptional circumstances to avoid disruption to supply, it may be possible to continue QP certification while corrective and preventive action is in progress; see Q&A on what is 'unexpected' deviation above.
To fulfil the criteria for the process of certification set out in Section 1 of Annex 16, the complete manufacturing and distribution supply chain of the medicinal product and its related active substance up to the stage of certification, should be documented and available for the Qualified Person. Supply chain records should provide adequate traceability and be available in a timely manner, to facilitate amongst others, quality defect investigations and product recalls as provided for in Chapter 8 of Part I of EU GMP, or requests of competent authorities. This means that these records should make it possible to identify, for active substances and medicinal products, all the entities, including suppliers and outsourced activities, involved in the manufacture of a specific batch of the drug product, in line with the registered supply chain.
In addition, and according to Chapter 1 and 5 of Part I of EU GMP, when establishing the supply chain traceability the associated risks should be formally assessed and periodically reviewed with appropriate risk-mitigation measures determined to mitigate any risks identified.
These questions and answers apply to EU/EEA QP certification or QP confirmation, as described in EU GMP, and specifically in Annex 16. It is applicable to the manufacture and importation of human and veterinary medicinal products as well as investigational medicinal products.
Remote batch certification / batch confirmation could be allowed if accepted by the national competent authority where the authorised site is located. Some competent authorities may have specific requirements regarding the implementation of remote batch certification / batch confirmation on a routine basis. Manufacturers and QPs should ensure that they comply with any applicable local requirements. In order to determine what requirements apply, manufacturers should consult with their national competent authority.
The following points should be taken into consideration:
The risk with regard to IT-security and data integrity for remote access is higher than for access within the controlled environment at the authorized site. Minimum requirements depend very much on the state of technology employed. The following requirements should be adapted to reflect current technological developments. Technical and organisational solutions which are not listed below but result in an appropriate level of security may also be acceptable:
There are currently no harmonized requirements concerning residency of QPs in the EU legislation. However, some Member States may have specific national requirements.
For retention purposes, it is not necessary to keep the full number of samples required in table 2.6.1.3 of the European Pharmacopoeia sterility test monograph to repeat the sterility test performed for release purposes, but only a sufficient quantity to allow the carrying out, on two occasions, of a confirmatory test using the minimum quantities described in table 2.6.1.2 of the monograph.
Firstly, the supervisory authority should grant such an exemption upon request from the manufacturer. The relevant authority may agree to this when one or more of the following criteria are met:
Parallel imported/distributed medicinal products will not be granted an exemption from keeping a fully packaged unit if the products have been re-packaged.This is because the exemption refers to “duplicate samples”, and in these cases no reference sample is required to be kept by the parallel distributor/importer.
On the other hand, where the secondary packaging of the source product is not opened by the parallel importer/distributor only samples of the additional packaging material used needs to be retained.
The original batch specific primary packaging material with print/imprint, if any, all the original batch specific secondary packaging materials e.g. labels and leaflets with print/imprint including Braille, and dosing aids, if any, must be kept.
The use of photocopies of the fully packaged unit to replace the retention sample are not acceptable as some details e.g. braille and holograms may not show correctly.
The requirements pertaining to retention samples for investigational medicinal products are covered in annex 13. There may be specific national requirements for compassionate use medicinal products, extemporary produced pharmacy products etc.
EU GMP principles and guidelines are laid down in Directive 2003/94/EC (human medicines) and Directive 91/412/EEC (veterinary products). These principles and guidelines are subject to further detailed guidance in the form of the EU GMP guideline with its annexes.
WHO publishes its own GMP guidance documents.
Although EU and WHO GMP guidance documents do differ in some details, the main principles remain the same. EU requirements fulfil all the recommendations of WHO.
Documents appearing in the EudraGMDP database are uploaded by the national competent authorities through a secure network guaranteeing their authenticity.For submissions to EU authorities paper documents are not required as a reference can be made to the EudraGMDP database.
EU authorities are aware that these documents are also used to support regulatory submissions in third countries and that various additional requirements, including apostilled copies are sometimes expected. In view of the integrity of entries in the EudraGMDP database, EU authorities strongly encourage reliance on the database.
Any concerns about a certificate/authorisation in the database should be addressed to the issuing authority.
GMP certificates are site-specific, but can be restricted to particular activities depending on the scope of the inspection (e.g., manufacturing activities related to a specific product). Directives 2001/82/EC and 2001/83/EC, as amended state that after every GMP inspection, and within 90 days of the inspection, a GMP certificate shall be issued to a manufacturer, if the outcome of the inspection shows that the manufacturer complies with GMP.
CMPs are product-specific certificates issued by the competent authority that granted the marketing authorisation. The European Medicines Agency issues CMPs on behalf of the European Commission for centrally authorised products.
CMPs are issued in the context of the World Health Organization certification scheme on the quality of pharmaceutical products moving in international commerce, to confirm the marketing-authorisation status of the products. These certificates also confirm the GMP compliance status of the manufacturing sites. CMPs are mainly used by companies to support applications to export their pharmaceutical products to countries with less-developed regulatory systems.
CEPs are certificates issued by the European Directorate for the Quality of Medicines and Healthcare (EDQM) to confirm that a certain active substance is produced according to the requirements of the relevant monograph of the European Pharmacopoeia or of the monograph on transmission spongiform encephalopathies.
CEPs can be used by companies when submitting an application for marketing authorisation, and replace much of the documentation required for the active substance in the marketing-authorisation dossier. GMP inspections of active-substance manufacturers can be requested by EDQM in the context of the CEP certification scheme.
No, the competent authority responsible for carrying out the inspection issues the GMP certificate, or makes an entry of non-compliance into the EudraGMP database.
All EU and EEA national competent authorities conducting inspections are obliged to enter GMP certificates in the EudraGMP database. Hence, any GMP certificate appearing in the database is mutually recognised and the database authenticates the certificate.
If a certificate cannot be found in the database, the issuing authority should be contacted.
In principle, a GMP non-compliance statement can only be lifted following a new inspection by an EU authority that results in the issue of a GMP certificate. In practice, this can present difficulties for manufacturers located in third countries.
For sites located in third countries the GMP non-compliance statement may mean that the site is no longer listed in marketing authorisations or applications and therefore there will be no reason for a new EU inspection. However, EU inspectorates acknowledge that the manufacturer may subsequently take remedial measures to bring the site into an acceptable level of compliance. As there is no intention to convey that the site continues to operate to an unacceptable level of non-compliance and given the absence of a new inspection trigger, the issuing authority will add a clarifying remark where a non-compliance statement appears in EudraGMDP over a prolonged period of time.
The Agency does not perform inspections. They are carried out on its behalf by the national competent authorities of the member states of the EEA, in connection with products under the centralised marketing-authorisation procedure.
Normally, the need for inspection under these circumstances is triggered by an application for a marketing authorisation. It may be possible to request an inspection on a voluntary basis, but as the competent authorities will have other priorities, there is no guarantee that such a request will be met.
To explore this possibility, the authorities of the Member State into which the product will be imported into the EEA should be approached. In any case, applicants are encouraged to approach the relevant authority in advance of submission in order to facilitate third-country inspection planning.
If the site is located in the EEA, the competent authority of the Member State where the site is located carries out the inspection.
For sites located in countries outside the EEA, the responsible authority for inspection (the 'supervisory authority') is the authority in whose territory the importing site is located. If the supervisory authority is not able to carry out the inspection for any reason, it can be delegated to another EEA competent authority.
If there is a mutual recognition agreement (MRA) in place between the countries where the site is located and the European Community, the results of GMP inspections carried out by the MRA partner authority are normally recognised by the EU authorities.
Data integrity enables good decision-making by pharmaceutical manufacturers and regulatory authorities.It is a fundamental requirement of the pharmaceutical quality system described in EU GMP chapter 1, applying equally to manual (paper) and electronic systems.
Promotion of a quality culture together with implementation of organisational and technical measures which ensure data integrity is the responsibility of senior management. It requires participation and commitment by staff at all levels within the company, by the company's suppliers and by its distributors.
Senior management should ensure that data integrity risk is assessed, mitigated and communicated in accordance with the principles of quality risk management. The effort and resource assigned to data integrity measures should be commensurate with the risk to product quality, and balanced with other quality assurance resource demands. Where long term measures are identified in order to achieve the desired state of control, interim measures should be implemented to mitigate risk, and should be monitored for effectiveness.
The following questions and answers describe foundational principles which facilitate successful implementation of existing guidance published by regulatory authorities participating in the PIC/S scheme. It should be read in conjunction with national guidance, medicines legislation and the GMP standards published in Eudralex volume 4.
The importance of data integrity to quality assurance and public health protection should be included in personnel training programmes.
Data risk assessment should consider the vulnerability of data to involuntary or deliberate amendment, deletion or recreation. Control measures which prevent unauthorised activity and increase visibility / detectability can be used as risk mitigating actions.
Examples of factors which can increase risk of data integrity failure include complex, inconsistent processes with open-ended and subjective outcomes. Simple tasks which are consistent, well-defined and objective lead to reduced risk.
Risk assessment should include a business process focus (e.g. production, QC) and not just consider IT system functionality or complexity. Factors to consider include:
This ensures that manual interfaces with IT systems are considered in the risk assessment process. Computerised system validation in isolation may not result in low data integrity risk, in particular when the user is able to influence the reporting of data from the validated system.
The decision which data influences may differ in importance, and the impact of the data to a decision may also vary. Points to consider regarding data criticality include:
For example: when making a batch release decision, data which determines compliance with critical quality attributes is of greater importance than warehouse cleaning records.
For example: for an oral tablet, active substance assay data is of greater impact to product quality and safety than tablet dimensions' data.
'Data lifecycle' refers to how data is generated, processed, reported, checked, used for decision-making, stored and finally discarded at the end of the retention period.
Data relating to a product or process may cross various boundaries within the lifecycle, for example:
Data integrity can be affected at any stage in the lifecycle. It is therefore important to understand the lifecycle elements for each type of data or record, and ensure controls which are proportionate to data criticality and risk at all stages.
The 'Data lifecycle' refers to the:
'Data Lifecycle' reviews are applicable to both paper and electronic records, although control measures may be applied differently. In the case of computerised systems, the 'data lifecycle' review should be performed by business process owners (e.g. production, QC) in collaboration with IT personnel who understand the system architecture. The description of computerised systems required by EU GMP Annex 11 paragraph 4.3 can assist this review. The application of critical thinking skills is important to not only identify gaps in data governance, but to also challenge the effectiveness of the procedural and systematic controls in place.
Segregation of duties between data lifecycle stages provides safeguards against data integrity failure by reducing the opportunity for an individual to alter, misrepresent or falsify data without detection.
Data risk should be considered at each stage of the data lifecycle review.
The following aspects should be considered when determining risk and control measures:
In the case of some computerised analytical and manufacturing equipment, data may be stored as a temporary local file prior to transfer to a permanent storage location (e.g. server). During the period of 'temporary' storage, there is often limited audit trail provision amending, deleting or recreating data. This is a data integrity risk. Removing the use of temporary memory (or reducing the time period that data is stored in temporary memory) reduces the risk of undetected data manipulation.
Controls over paper records are discussed elsewhere in this guidance.
Computerised system controls may be more complex, including setting of user privileges and system configuration to limit or prevent access to amend data. It is important to review all data access opportunities, including IT helpdesk staff, who may make changes at the request of the data user. These changes should be procedurally controlled, visible and approved within the quality system.
Data should be protected from possibility of intentional or unintentional loss or amendment during transfer to other systems (e.g. for processing, review or storage). Paper records should be protected from amendment, or substitution. Electronic interfaces should be validated to demonstrate security and no corruption of data, particularly where systems require an interface to present data in a different structure or file format.
Does the person processing the data have the ability to influence what data is reported, or how it is presented.
The following aspects should be considered when determining risk and control measures:
Data processing methods should be approved, identifiable and version controlled. In the case of electronic data processing, methods should be locked where appropriate to prevent unauthorised amendment.
The processing method should be recorded. In situations where raw data has been processed more than once, each iteration (including method and result) should be available to the data checker for verification.
Even 'validated systems' which do not permit the user to make any changes to data may be at risk if the user can choose what data is printed, reported or transferred for processing. This includes performing the activity multiple times as separate events and reporting a desired outcome from one of these repeats.
Data presentation (e.g. changing scale of graphical reports to enhance or reduce presentation of analytical peaks) can also influence decision making, and therefore impact data integrity.
The following aspects should be considered when determining risk and control measures:
The format of the original data (electronic or paper) should be preserved, and available to the data reviewer in a manner which permits interaction with the data (e.g. search, query). This approach facilitates a risk-based review of the record, and can also reduce administrative burden for instance utilising validated audit trail 'exception reports' instead of an onerous line-by-line review.
This may present opportunity for data amendment which is not subsequently visible to the data reviewer. Additional control measures should be implemented to reduce risk of undisclosed data manipulation.
This should include any data from failed or aborted activities, discrepant or unusual data which has been excluded from processing or the final decision-making process. Visibility of all data provides protection against selective data reporting or 'testing into compliance'.
This ensures that the final result obtained from raw data is based on good science, and that any data exclusion or changes to processing method is based on good science. Visibility of all processing information provides protection against undisclosed 'processing into compliance'.
The following aspects should be considered when determining risk and control measures:
If data acceptability decisions are taken before a record (raw data or processed result) is saved to permanent memory, there may be opportunity for the user to manipulate data to provide a satisfactory result, without this change being visible in audit trail. This would not be visible to the data reviewer.
This is a particular consideration where computerised systems alert the user to an out of specification entry before the data entry process is complete (i.e. the user 'saves' the data entry), or saves the record in temporary memory.
The following aspects should be considered when determining risk and control measures:
Storage of data (paper or electronic) should be at secure locations, with access limited to authorised persons. The storage location must provide adequate protection from damage due to water, fire, etc.
Data security measures should be at least equivalent to those applied during the earlier Data lifecycle stages. Retrospective data amendment (e.g. via IT helpdesk or data base amendments) should be controlled by the pharmaceutical quality system, with appropriate segregation of duties and approval processes.
Back-up arrangements should be validated to demonstrate the ability to restore data following IT system failure. In situations where metadata (including relevant operating system event logs) are stored in different file locations from raw data, the back-up process should be carefully designed to ensure that all data required to reconstruct a record is included.
Similarly, 'true copies' of paper records may be duplicated on paper, microfilm, or electronically, and stored in a separate location.
A technical agreement should be in place which addresses the requirements of Part I Chapter 7 and Part II Section 16 of the GMP guide.
The following aspects should be considered when determining risk and control measures:
This will be influenced by regulatory requirements and data criticality. When considering data for a single product, there may be different data retention needs for pivotal trial data and manufacturing process / analytical validation data compared to routine commercial batch data.
Any disposal of data should be approved within the quality system and be performed in accordance with a procedure to ensure compliance with the required data retention period.
There is no requirement for a specific procedure, however it may be beneficial to provide a summary document which outlines the organisations total approach to data governance.
A compliant pharmaceutical quality system generates and assesses a significant amount of data. While all data has an overall influence on GMP compliance, different data will have different levels of impact to product quality.
A quality-risk management (ICH Q9) approach to data integrity can be achieved by considering data risk and data criticality at each stage in the Data lifecycle. The effort applied to control measures should be commensurate with this data risk and criticality assessment.
The approach to risk identification, mitigation, review and communication should be iterative, and integrated into the pharmaceutical quality system. This should provide senior management supervision and permit a balance between data integrity and general GMP priorities in line with the principles of ICH Q9 & Q10.
The main regulatory expectation for data integrity is to comply with the requirement of ALCOA principles. The table below provide for each ALCOA principle the link to EU GMP references (Part I, Part II and Annex 11):
|
Basic Requirements for Medicinal Products (Part I): Chapter 4(1) / Chapter 6(2) |
Basic Requirements for Active Substances used as Starting Materials (Part II) : Chapter 5(3) / Chapter 6(4) |
Annex 11 (Computerised System) |
|
|
Attributable (data can be assigned to the individual performing the task) |
[4.20, c & f], [4.21, c & i], [4.29, e] |
[6.14], [6.18], [6.52] |
[2], [12.4], [15] |
|
Legible (data can be read by eye or electronically and retained in a permanent format) |
[4.1], [4.2], [4.7], [4.8], [4.9], [4.10] |
[5.43] [6.11], [6.14], [6.15], [6.50] |
[7.1], [9], [10], [17] |
|
Contemporaneous (data is created at the time the activity is performed) |
[4.8] |
[6.14] |
[12.4], [14] |
|
Original (data is in the same format as it was initially generated, or as a 'verified copy', which retains content and meaning) |
[4.9], [4.27], [Paragraph "Record"] |
[6.14], [6.15], [6.16] |
[8.2], [9] |
|
Accurate (data is true / reflective of the activity or measurement performed) |
[4.1], [6.17] |
[5.40], [5.45], [6.6] |
[Paragraph "Principles"], [5], [6], [10], [11] |
The template (blank) forms used for manual recordings may be created in an electronic system (Word, Excel, etc.). The corresponding master documents should be approved and controlled electronically or in paper versions. The following expectations should be considered for the template (blank) form:
The distribution of template records (e.g. 'blank' forms) should be controlled. The following expectations should be considered where appropriate, based on data risk and criticality:
Computerised systems should be designed in a way that ensures compliance with the principles of data integrity. The system design should make provisions such that original data cannot be deleted and for the retention of audit trails reflecting changes made to original data.
In the case of data generated from an electronic system, electronic data is the original record which must be reviewed and evaluated prior to making batch release decisions and other decisions relating to GMP related activities (e.g. approval of stability results, analytical method validation etc.). In the event that the review is based solely on printouts there is potential for records to be excluded from the review process which may contain un-investigated out of specification data or other data anomalies. The review of the raw electronic data should mitigate risk and enable detection of data deletion, amendment, duplication, reusing and fabrication which are common data integrity failures.
Example of an inspection citing:
Raw data for HPLC/GC runs which had been invalidated was stored separately to the QC raw data packages and had not been included in the review process.
In the above situation, the procedure for review of chromatographic data packages did not require a review of the electronic raw data or a review of relevant audit trails associated with the analyses. This lead to the exclusion of records from the review process and to lack of visibility of changes made during the processing and reporting of the data. The company was unable to provide any explanation for the data which had been invalidated.
Yes. The principles of quality risk management may be applied during the review of electronic data and review by exception is permitted, when scientifically justified.
Exception Reporting is used commonly as a tool to focus the review of electronic data such as (but not limited to) electronic batch records. Exception reporting rapidly highlights to the reviewer one of the most critical elements of batch review, i.e. the exceptions. The level of review of the full electronic batch record can vary based on the exceptions as well as the level of confidence and experience with a particular process. Appropriate testing and validation must be completed for the automated system and the output Batch Exception Report to ensure its functionality meets the business and regulatory requirements as per GMP.
Ongoing compliance with the company's data governance policy/procedures should be reviewed during self-inspection, to ensure that they remain effective. This may also include elements of the Data lifecycle discussed in Q3-Q9.
Data integrity requirements should be incorporated into the company's contractor/vendor qualification/assurance program and associated procedures.
In addition to having their own data governance systems, companies outsourcing activities should verify the adequacy of comparable systems at the contract acceptor. The contract acceptor should apply equivalent levels of control to those applied by the contract giver.
Formal assessment of the contract acceptors competency and compliance in this regard should be conducted in the first instance prior to the approval of a contractor, and thereafter verified on a periodic basis at an appropriate frequency based on risk.
The recipient should have knowledge of the systems and procedures implemented at the supplier for the generation of the CoA. Arrangements should be in place to ensure that significant changes to systems are notified and the effectiveness of these arrangements should be subjected to periodic review.
Data related to activities which are outsourced are routinely provided as summary data in a report format (e.g. CoA). These summary documents are reviewed on a routine basis by the contract acceptor and therefore the review of data integrity at the contract acceptor site on a regular periodic basis (e.g. during on-site audit) takes on even greater significance, in order to build and maintain confidence in the summary data provided.
Using the principles of QRM to assess data criticality and risk, the company should include assessment of data governance systems implemented by the service provider when making decisions on service contracts. This may be achieved by on-site audit or desk-based assessment of information submitted by the service provider.
It is considered that the company should evaluate the risk to its products manufactured/released using the principles of quality risk management. Risk assessments should be made available to Inspectors, on request.
Depending on the outcome of the risk assessment, appropriate action should be taken which may entail delisting the contractor from the approved contractor list. In the event that abnormal disruption in supply may result from a contractor compliance situation, relevant regulatory authorities should be consulted in this regard.
All actors in the supply chain play an important part in overall data integrity and assurance of product quality.
Data governance systems should be implemented from the manufacture of starting materials right through to the delivery of medicinal products to persons authorised or entitled to supply medicinal products to the public.
Relative responsibilities and boundaries should be documented in the contracts between the relevant parties. Final responsibility of ensuring compliance throughout the supply chain rests with batch certifying QP.
No. According to the Guideline on declaration of storage conditions, marketing authorisation holders have to provide stability data for storage conditions at 25°C / 60% relative humidity (RH), or 30°C / 65% RH (long term) and 40°C / 75% RH (accelerated), in order to justify not including a statement in the medicinal product labelling.
This stability data is generated according to the temperature and humidity conditions of climate zone I (temperate) and II (Mediterranean/subtropical) in Europe. For more information, see the World Health Organization Expert Committee on Specifications for Pharmaceutical Preparations forty-third report, Annex 2: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products.
No labelling statement means that controls should be in place to maintain conditions relevant to climate zones I and II. Consequently, the temperature should be monitored during storage and transport. Appropriate limits should be set for temperature monitoring to ensure that product stability is not adversely affected.
No. The Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use state in paragraph 10.4 v): “procedure for verifying that their supplying wholesale distributors hold a distribution authorisation, their supplying manufacturers or importers hold a manufacturing authorisation and their customers are authorised to supply medicinal products in the Member State concerned”.
That means that both suppliers and customers should be located in the EEA. Brokering activities regarding both supplier and customer located outside the EEA fall outside the scope of the EU legislation (GDP guidelines).
No. The Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use state in paragraph 10.4 iv): “procedure for ensuring that medicinal products brokered have a marketing authorisation”.
That means that the medicinal products must have a marketing authorisation in at least one of the EEA member states.
Wholesalers and others buying or receiving medicinal products must be aware of the risk that products offered to them are falsified, illegitimate or in other ways not of full quality. However, it is often difficult to unveil if an offer is suspicious.
Some guidance regarding suspicious offers may be understood from article 5.2 in the guidelines for European Union (EU) GDP guidelines for human medicinal products.
When entering into a new contract with new suppliers, the wholesale distributor should carry out ‘due diligence’ checks in order to assess the suitability, competence and reliability of the other party. Attention should be paid to:
Similar guidance is given in regulation for European Union (EU) GDP regulation for veterinary medicinal products in article 21.2.
When entering into a contract with new suppliers, the persons referred to in Article 1(2) shall carry out so called due diligence checks in order to assess the suitability, competence and reliability of the other party. The due diligence checks shall consider:
Additionally, a buyer of medicinal products may consider the following aspects. Offers corresponding to the points below may be suspicious.
To verify a wholesalers identity, use the EudraGMDP database. To verify a brokers identity use the repositories indicated through links to NCAs provided by HMA.
Article 5.2 in the GDP guidelines for human medicinal products states the following:
Wholesale distributors must obtain their supplies of medicinal products only from persons who are themselves in possession of a wholesale distribution authorisation, or who are in possession of a manufacturing authorisation which covers the product in question (Article 80(b) of Directive 2001/83/EC).
Article 101 of regulation (EU) 2019/6 for veterinary medicinal products states that wholesale distributors shall obtain veterinary medicinal products only from holders of a manufacturing authorisation or from other holders of a wholesale distribution authorisation.
Wholesale distributors receiving medicinal products from third countries for the purpose of importation, i.e. for the purpose of placing these products on the EU market, must hold a manufacturing authorisation (Article 40(3) of Directive 2001/83/EC and article 88 (1c) regulation 2019/6).
Even if it is not mentioned explicitly, this prohibits the supply of medicinal products from pharmacies (or others supplying medicinal products to the public) to wholesalers, except for returns described in 6.3(ii) of the human GDP Guideline or article 30(c) of the veterinary GDP regulations, i.e. return of medicinal products from a pharmacy to the wholesaler that supplied the product.
Any wholesale distributor or broker who learns of a substantiated suspicious offer should immediately contact the national competent authority as well as the marketing authorisation holder.
This follows from articles 5.1, 6.1, 6.4, 10.2, 10.4 of European Union (EU) GDP guidelines for human medicinal products, and articles 10.3 18.1 (m), 20.1, 31 in regulation (EU) 2021/1248 on wholesaler of veterinary medicinal products.
The distributor or broker should contact the authorities and marketing authorisation holder regardless if they are themselves being offered suspected falsified products, or if they learn of suspected offers being made to others, e.g. when verifying unique identifiers of packs on behalf of another actor.
Wholesalers shall ensure first that all veterinary medicinal products they distribute in the Union are covered by a marketing authorisation, a registration or another kind of authorisation (parallel trade, importation authorisation…). In addition, they shall ensure that veterinary medicinal products intended for the EU and EEA countries should not be transferred to saleable stock before assurance has been obtained that they are authorised for sale.
According to article 97 of Regulation 2019/6, the Qualified person responsible for manufacturing and batch release shall draw up a control report establishing that each batch of the veterinary medicinal products is manufactured in compliance with good manufacturing practice, and tested in compliance with the terms of the marketing authorisation. Such control reports shall be valid throughout the Union.
Batches of veterinary medicinal products which have undergone the controls referred to in Art. 97 of regulation 2019/6 in a Member State are exempt from the controls in another Member State where they will be marketed if they are accompanied by the control reports signed by the qualified person.
In this context, wholesalers shall check that batches of veterinary medicinal products coming from another member state are be accompanied by evidence that the manufacturer’s qualified person has certified the finished product batch. This check could be done by different means : paper based check (copy of controls reports), electronically check or other equivalent system as agreed with the supplier (manufacturer or wholesaler).
The requirements for registration of manufacturers and importers of active substances (and active substance intermediates, i.e crude active substances or other active substance intermediates, the manufacturing of which is described in a regulatory dossier) as required under Article 52a of Directive 2001/83/EC is summarised in the table below.
| Active substances for human use | Active substance intermediates for human use | ||
|---|---|---|---|
| Registration | Manufacturer | Yes | Yes |
| Distributor | Yes | No | |
| Importer | Yes | No |
EMA’s Committee for Advanced Therapies (CAT), together with the GMDP Inspectors Working Group and the Biologics Working Party, have prepared a questions-and answers document on the use of out-of-specification batches of authorised cell or tissue-based ATMPs:
Yes, active substances used as starting materials in veterinary medicinal products imported or manufactured in the Union1 have to be manufactured in accordance with GMP for active substances. This obligation, set out in Article 93(1)(j) of the Regulation applies regardless of whether the active substances are manufactured in the Union or in third countries. This obligation already existed under Directive 2001/82/EC. 2
Until the specific GMP for veterinary medicinal products and active substances used as starting materials referred to in Article 93(2) of the Regulation (EU) 2019/63 (the Veterinary Medicines Regulation) are adopted, the Part II of the Good Manufacturing Practice Medicinal Products for Human and Veterinary Use on Basic Requirements for Active Substances used as Starting Materials, as well as relevant annexes, applies.4
1 For the purposes of this document, reference to the Union should be understood as including also the EEA countries.
2 Directive 2001/82/EC of the European Parliament and of the Council on the Community code relating to veterinary medicinal products (OJ L 311, 28.11.2001, p. 1).
3 Regulation (EU) 2019/6 of the European Parliament and of the Council on veterinary medicinal products and repealing Directive 2001/82/EC, OJ L4, 7..01.2919, p.4.
4https://ec.europa.eu/health/medicinal-products/eudralex/eudralex-volume-4_en.
Yes, the Veterinary Medicines Regulation requires manufacturers and importers of veterinary medicinal products to:
Manufacturing sites of active substances established outside the Union territory are not required to register their activities in accordance with Article 95 of the Regulation. However, to the extent that the active substances are used in veterinary medicinal products marketed in the Union, the manufacturer or importer of the relevant veterinary medicinal products is required to audit these sites.
The existence of valid GMP certificate for a manufacturing site of active substance(s), issued by a Union authority or by the authority of a third country in the context of a valid mutual recognition agreement, can be taken into consideration by manufacturers and importers of veterinary medicinal products, together with other supporting information in a risk-based approach, to determine the extent of the auditing obligations of manufacturers of finished medicinal products foreseen in Article 93(1)(l) of the Regulation (i.e. to establish priorities for its own audit programme of suppliers of active substances).3
While manufacturing sites of active substances used as starting materials in veterinary medicinal products may, therefore, have an interest to obtain a GMP certificate from a Union competent authority, reference is made to question 5, in connection with the requests for voluntary inspections.
1 Article 93(1)(k) and Article 95 of the Veterinary Medicines Regulation.
2 Article 93(1)(l). It is noted that the conduct of audits was already foreseen as part of the recommendations in the Good Manufacturing Guidelines (e.g. Section 5.29 of the Chapter 5, Part I of the EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use).
3 Article 93(1)(l) and Article 95 of the Veterinary Medicines Regulation.
4 Reference is also made to EMA Q&A on EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances, question n°2.
Article 94(1) to (3) of the Veterinary Medicines Regulation describes the procedure to issue a GMP certificate, after a successful inspection has been conducted. If the outcome of the inspection is that the site does not comply with EU GMP, this information shall be entered into the manufacturing and wholesale distribution database.
Pursuant to Article 2(2) of the Regulation, the same procedure applies for certificates for manufacturing sites of veterinary medicinal products and for certificates for manufacturing sites of active substances used as starting materials, regardless whether they are established in the Union or outside.
For aspects relevant to requests of voluntary inspections, reference is made to question 5.
Manufacturing sites of veterinary medicinal products must have an EU GMP certificate, regardless of whether they are located in the Union or outside. Specifically, Article 94(5) of the Veterinary Medicines Regulation requires that importers of veterinary medicinal products ensure that any manufacturing site of such products established outside the Union has a GMP certificate issued by Union competent authorities, unless a mutual recognition agreement between the Union and the third country applies.1
However, manufacturing sites that only produce active substances used as starting materials in veterinary medicinal products are not required to have a GMP certificate.2 Compliance with EU GMP for active substances must however be ensured as explained in questions 1 and 2.
1 Reference is also made to the Compilation of Union Procedures on Inspections and Exchange of Information:
2 Article 2(2) provides that Articles 94 and 95 apply also to active substances used as starting materials. This cross-reference should be read in conjunction with the specific wording of the cross-referred provisions. To this effect, it is noted that Article 95 specifically deals with active substances used as starting materials, while paragraphs (1) to (4) of Article 94 are neutrally worded and apply therefore to both finished products and active substances. In contrast, paragraph (5) of Article 94 explicitly refers to veterinary medicinal products and not to active substances.
Furthermore, to consider that manufacturing sites of active substances established outside the Union should have a GMP certificate would contradict the general scheme of the Regulation, including the requirement for audits (new obligation for importers and manufacturers of veterinary medicinal products to guarantee that active substances have been manufactured in accordance with GMP) and would run against one of the main objectives of the legislation; namely, to increase the availability of veterinary medicinal products.
Yes. The request for the inspection should be made to the EEA competent authority where the site is located or, in case of sites located in third countries, to a competent authority where the active substance used as starting material is used in the manufacture of veterinary medicinal products, or the Member State where the importer is established. If this is not the case, any EEA authority can be approached.
There is no guarantee that such a request will be fulfilled since competent authorities primarily use risk-based principles to plan inspections. Thus, when a manufacturer of active substance(s) used as starting material in veterinary medicinal products applies for a voluntary inspection, this does not constitute an obligation for the competent authority to trigger an inspection.
The procedure for issuing an EU GMP certificate under paragraphs (1) to (3) of Article 94 is applicable to manufacturers of active substances used as starting materials (see also question 3).
Finally, it is stressed that manufacturers/importers are required to ensure that only active substances manufactured in accordance with applicable GMPs are used.1 An inspection of the active substance manufacturer by an EEA authority does not exempt a manufacturing authorisation holder from this responsibility but, as explained in question 2, may be relevant to determine the extent of the audits.
1 Article 93(1)(j).
Yes. Article 94(4) of the Veterinary Medicines Regulation (in conjunction with Article 2(2) thereof) encompasses both manufacturing sites of finished veterinary medicinal products and manufacturing sites of active substances used in veterinary medicinal products. It follows that national competent authorities, the Agency, or the European Commission can request an inspection of a manufacturer of active substance used as a starting material, including third country manufacturers.
These inspections may be carried out:
Yes, when there is a MRA is in place covering GMP for active substances, the outcome of inspections performed by the MRA partner authority will be taken into consideration when deciding whether an inspection of a manufacturing site of active substances used as starting materials is necessary.