The contracting of services to third parties (outsourcing) is becoming more and more important due to the increasingly stringent quality and safety requirements that apply to medicinal products and the increasing cost pressure in health care. Outsourcing ensures that the contract giver and the contract acceptor can focus on their core competencies. It is useful when special technologies or expensive equipment are required, provides access to third-party expertise and, at the same time, frees up in-house resources.
The legal requirements for outsourcing activities are outlined in EU Directive 2017/1572, and Chapter 7 of the EU GMP Guide (Section C.3.1.7) contains additional information. As a rule, the responsibility for the outsourced activities remains with the contract giver.
The initial audit of a service provider focuses on its QA system and the general processes associated with it. Follow-up audits should be risk-based. A key objective of the audit is to get to know the contractual partner personally and thus create a basis of trust for further cooperation.
The contract giver or their qualified person bear the ultimate responsibility for ensuring that a medicinal product has been manufactured and tested in compliance with all legal requirements. For this reason, it is vital that all of the processes required to select, qualify and monitor service providers are described in the QA system of the contract giver. Furthermore, the relevant tasks and responsibilities must be documented in a limitation of liability agreement (GMP contract). This also includes the sharing of information between the parties. The contract giver is obliged to monitor the quality of the services provided continuously and check during the product quality review that the contractual agreements are up to date.
The limitation of liability agreement (GMP contract) must ensure that all of the activities are assigned to the interested parties in such a way that there are no gaps or overlaps. The handling of changes and deviations requires particularly clear rules.
In addition to the limitation of liability contract, other contracts are required, in particular, the commercial contract as well as confidentiality agreements.
(Frank Böttcher, PhD; Martin W. Wesch, Professor and Doctor of Law)
European medicinal product manufacturers are obliged to use as starting materials only active substances that have been manufactured in compliance with EU GMP requirements. This proof is provided by EU GMP certificates, GMP certificates from authorities in third countries with a mutual recognition agreement (MRA and ACAA) and written confirmations from authorities in third countries.
EU GMP certificates attest to a manufacturer GMP compliance for the listed manufacturing activities at the time of a regulatory inspection. They are issued by EU monitoring authorities within 90 days of an inspection of the active substance manufacturer and entered in the European database EudraGMDP. They are usually valid for three years.
A GMP certificate from an MRA or ACAA partner country is equivalent to an EU GMP certificate and can be substituted for it.
A written confirmation must be submitted for all active substances from third countries, including those whose manufacturer has a current EU GMP certificate or MRA or ACAA GMP certificate.
GMP certificates issued by accreditation bodies or consultancies have no official validity.
GMP certificates issued by other third countries, WHO or even accreditation bodies or consultants are not recognised as evidence of GMP compliance in the EU.
(Sabine Paris, PhD)
This chapter on biotechnological active substances encompasses a large number of additional regulatory requirements on GMP-compliant manufacturing of these products, which must be taken into account. Due to regulations to be observed elsewhere, these requirements are not always specifically related to GMP. Especially when living, sometimes pathogenic organisms, cells, tissues or infectious materials are involved, the regulations in effect serve not only to safeguard the product, but also to ensure the safety of employees and to protect the environment.
The variety of different products and associated manufacturing processes is clearly greater than in the classic manufacture of active substances. Particularly the origin and makeup of the starting and raw materials used here are often specifically related to the product. It follows that the controls and tests to be applied to these materials differ accordingly, as do the resultant control strategies of the relevant manufacturing process.
For these reasons it is considerably more difficult to create an unequivocal structure and clear outline of the applicable regulations on GMP-compliant manufacturing of biotechnological products. Instead, especially in this area the important thing is to define individual, specifically product-related requirements for starting and raw materials, the manufacturing process, the machines used and the control strategies to be applied. Quality risk management is crucial to this.
This chapter is intended to filter out the specific GMP requirements that have to be taken into consideration for a certain product or group of products and to combine them with general GMP regulations.
(Rainer Gnibl, PhD)
This revised version 20 of the Q&A document on safety features for medicinal products, comes along with one new Q&A on UI verification of authenticity.
Question 5.14 “Is it allowed to verify the authenticity of the UI when the product is not in physical possession?” is answered with “Yes, but only as an additional check to Article 20 of Commission Delegated Regulation (EU) 2016/161.”
As a minimum requirement the article obligates wholesalers to verify the authenticity of the UI for at least the medicinal products in their physical possession which are
A wholesaler may verify the authenticity of products of other origins than those addressed in Article 20 via the UI when the product is not in physical possession. This should be considered an additional check.
It does not exempt from the obligation to verify the UI once the product is in physical possession and can thus not replace it. Only authorised suppliers located in the EU can put medicinal products on the market in the EU. Verifying the UI of packs located outside the EU does not replace import testing and batch certification after import by authorised manufacturers.
The revision includes an update of Q&A 10 on the limits for nitrosamines in medicinal products and introduces a new Q&A 21 on the approach to control presence of nitrosamine while the AI (acceptable intake) is being established.
Q&A 10: Which limits apply for nitrosamines in medicinal products?
Q&A 21: What is the approach to control the presence of nitrosamines until a substance specific AI is established?
In practice: When competent authorities are notified about a product containing a new N-nitrosamine exceeding the TTC limit of 18 ng/day, no market actions may be required for batches with N-nitrosamine levels ≤ 178 ng/day at the MDD pending the agreement of the AI. The adoption of the t-AI is not automatic and is evaluated by the authorities at the time of notification. Use of the t-AI beyond 12 months will require additional consultation with competent authorities. The t-AI should not be used as a target for development of validated analytical methods to quantify new nitrosamines since the long-term limits adopted by CHMP might ultimately be lower than the t-AI.