Questions and answers: GMP compliance for active substances (EU GMP guide part II)

Questions and answers

Basic requirements for active substances used as starting materials: GMP compliance for active substances

1. How can GMP compliance for active-substance manufacturers be demonstrated? H+V April 2011

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.

2. Do I need to perform an audit of an active substance supplier if it has been inspected by an inspectorate from a European Economic Area (EEA) Member State and a valid GMP certificate is available? H+V July 2006

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.

3. Is it acceptable to perform a remote assessment based on, for example, questionnaires, review of documents, Internation Organization for Standardization 9000 certification, results of analytical testing and historical experience with the supplier? H+V July 2006

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.

4. How do the new requirements affect importers of medicinal products? H+V July 2006

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.

5. Is it possible to ask for a voluntary inspection of an active substance manufacturer? H+V February 2015

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.

6. 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 circumstances 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.

7. What kind of GMP documentation is needed for an active-substance manufacturer that performs sterilisation of an active substance? July 2010

The GMP basic requirements for active substances used as starting materials (EU GMP guideline part II) only applies to the manufacture of sterile active substances up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not covered by this guideline and should be performed in accordance with GMP for medicinal products (Commission Directive 2003/94/EC as interpreted in the basic requirements for medicinal products including annex 1 of the EU GMP guideline part I). This implies that for any active-substance manufacturer that performs sterilisation and subsequent aseptic handling of the active substance, a valid manufacturing authorisation or GMP certificate from an EEA authority or from an authority of countries where MRA or other Community arrangements apply has to be submitted.

The active-substance manufacturer also has to submit data on the sterilisation process of the active substance (including validation data) to the marketing-authorisation applicant or holder for inclusion in the dossier submitted for the finished product and approval by the licensing authorities.

8. During inspections, why do inspectors sometimes ask to see reports of audits of active substance manufacturers carried out by the medicinal product manufacturer? H+V May 2013

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.

9. What expectations do inspectors have for the content of reports of audits of active substance manufacturers carried out by the medicinal-product manufacturer? H+V May 2013

As a minimum, the following is expected to be included in the report:

• The full postal address of the site. The auditors must be identified by full name and their employer recorded. If the audit is conducted on behalf of other parties this should be clear in the report. Where an audit report is obtained through a third party, the manufacturing-authorisation holder is responsible for ensuring the validity and impartiality of the audit report. The identity of key staff participating in the audit should be recorded along with their roles.The full contact details of the person through which the audit was arranged should be recorded including contact details (e-mail address, telephone number). The dates of the audit should be recorded, with the full-day equivalents clarified if full days were not spent on site. A justification should be recorded for the duration of the audit. If, in exceptional circumstances, the audit had to be restricted to fewer days on site than required by the scope of the audit, the reasons should be explained and the conclusions with respect to the GMP status of the site should be justified.ackground information on the active substance manufacturer should be recorded; this should include the company ownership, the age of the site, the number of staff employed in total and for the specific products being audited. The role of the site in manufacture of the active substances being audited should also be clarified for each of the active substances being audited, e.g. if the site performs the full manufacture or only part of the manufacture.
• The scope of the audit should be clearly stated e.g. what activities (against European Union GMP part II / International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q7 chapters) were covered. The activities which were not covered by the audit should also be clearly recorded. Auditors should identify the high risk areas for audit specific to the site or products being audited. For example, these could include but not be limited to:
  • process, cleaning or validation;
  • risk of cross-contamination with other active substances or other substances;
  • potential for generation of unknown impurities;
  • risk of mix-up of materials and products through materials handling or packing;
  • change control;
  • deviation recording or management;
  • security sealing of active substance containers and security or temperature control of shipments.
• Subsequent audits conducted as part of the ongoing supplier audit program may have a reduced scope focusing on the highest risk areas. In such cases the highest risk areas should be identified and justified.
• A list should be recorded of all active substances directly included in the audit scope plus other active substances or intermediates (or other products) manufactured at the site.

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.

• Dates of any previous audit conducted by or on behalf of the same manufacturing-authorisation holder should be recorded. If any of the audits did not conclude with a positive GMP compliance status, a brief summary of the reasons for this should be recorded.
• Each of the applicable sections of EU GMP part II should form sections of the report with a summary of what was examined, the key findings and compliance with the requirements of each section. The report should clearly state findings against each activity audited with particular focus on the high risk areas. Any GMP deficiency identified during the audit must be clearly recorded with its criticality defined. An explanation should be given, in the report or in a supporting standard operating procedure, of the categorisation system used to classify deficiencies, e.g. critical, major or minor.
• Responses to the audit by the active-substance manufacturer should be reviewed by the auditors. Corrective and preventative actions and timescales for completion should be assessed by the auditors to establish whether these are appropriate to the findings. Further clarification or evidence of completion should be requested, commensurate to the risk.
• A summary assessment of the status of corrective and preventive actions should be recorded by the auditors once these have been received and assessed. An overall recommendation should be made in the final report. The summary should include whether the auditor regards the actions as satisfactory. The responsible QP should ensure that he or she, or someone to whom it is delegated, is in agreement with the overall recommendation of the final report. The QP must not release the relevant medicinal products without knowledge of a positive recommendation from the auditors. This recommendation should include the GMP compliance status of the site and whether any reduced controls on materials receipt at the finished product manufacturing site are supported by the auditors.
• A proposed re-assessment period should be recommended.
• The final report should be signed and dated by, at least, the lead auditor.

10. How should active substance auditors be qualified? H + V May 2013

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.

11. What is the frequency for the routine re-inspection of an active substance manufacturer? H+V February 2015

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 substanceslocated 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.

12. What are the GMP requirements to be applied to the formulation of biological active substances with excipients, when described in the active substance section of a registration dossier? H+V February 2017

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:

• Particular emphasis should be put on the management of the constitutive excipients of the formulated active substance. Specifications should be defined for excipients according to GMP Part I., 4.14 and the monographs of the European Pharmacopoeia should be applied. The approval, maintenance and audit of excipient suppliers should be based on quality risk management, in accordance with GMP Part I, 5.29 and the EU guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use. An agreement between the medicinal product manufacturer and the excipient manufacturer should be established in accordance with GMP Part I, 5.28.

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)).

• Consideration should be given to the inclusion of batches of a finished medicinal product manufactured from formulated active substances, stored for the maximum holding time, in the ongoing stability program of the medicinal product, in accordance with GMP Annex 2, 67 and GMP Part I., 6.28.
• When outsourced, the manufacture of a formulated active substance should be managed in the same way as the outsourcing of the manufacture of an intermediate medicinal product, through full application of the requirements of Chapter 7 of the GMP part I guideline.

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Referance : European Medicines Agency’s answers to frequently asked questions, as discussed and agreed by the Good Manufacturing Practice (GMP) / Good Distribution Practice (GDP) Inspectors Working Group