Batch release of medicinal products

The batch release of a medicinal product is the final stage of manufacturing before it enters the market and thus reaches the patient. The qualified person (QP) pursuant to Section 14 of the German Medicinal Products Act (§ 14, AMG) is responsible for ensuring that each batch of a medicinal product has been manufactured and tested in accordance with applicable drug law. This includes compliance with legal requirements such as EU Directive 2001/83/EC on the Community code relating to medicinal products for human use, implemented in national legislation (e.g., AMG, AMWHV), as well as the guidelines for good manufacturing practice (GMP guidelines). Annex 16 of the EU GMP Guidelines outlines detailed requirements for batch release and certification of a medicinal product by a Qualified Person.

QP requirements

Persons acting as a QP must meet specific requirements concerning their expertise, as laid out in section 15 of German Medicinal Products Act (§ 15, AMG). This includes either a pharmacist’s license or proof of a comparable academic degree complemented by documented education and knowledge in specific core subjects as pharmaceutical technology, pharmacology, and microbiology, along with a minimum of two years of practical experience. According to EU GMP Annex 16, any QP involved in the certification, or confirmation of a batch must have detailed knowledge of the steps for which they are taking responsibility. QPs should be able to prove their continuous training regarding the product type, production processes, technical advances and changes to GMP. Furthermore, the QP must be notified to and accepted by a competent authority (§§ 14 and 20 AMG).

Which prerequisites must be fulfilled prior to release?

Before a finished medicinal product can be manufactured and released for market use, the following requirements are to be fulfilled.

Supplier Qualification / Contracts: Since manufacturers of the medicinal products and MAHs (marketing authorization holders) are often not the same entities, and other parties (e.g., contract laboratories, distribution companies) may also be involved, supplier qualification is essential. Before any supplier is considered, it is checked whether they can provide the required services, e.g., by checking the availability of all necessary certificates (e.g., GMP certificates, GDP certificates). In case the supplier or service provider meets the criteria, responsibilities are clearly defined in quality assurance agreements (QAA). The content of a QAA must be tailored to the specific product(s) and customer. To avoid future problems, the certifying QP should already be involved at this stage. Supplier qualification typically includes audits that encompass an assessment of the supplier’s quality management system. Regular requalification involves check of the validity of certificates, reviewing contracts for any need for revision, and conducting of follow-up audits. Any deviations/non-conformances identified during the audits are evaluated by the auditors and documented in the audit report. The audited company then draws up a CAPA (Corrective and Preventive Action) plan in which it addresses the findings, defines corrective and preventive actions, sets up a timeline for their implementation and then rectifies the non-conformances.

Marketing Authorisation / Registration: Each finished medicinal product must be authorized or registered. As part of this process, quality-related elements such as manufacturing and testing procedures, manufacturers and laboratories, and specifications are defined. Only after approval by a competent authority (e.g., BfArM, EMA, PEI), the medicinal product may be placed on the market. Any changes to information specified in the dossier must be notified to the authority as variations.

Importation: In case medicinal products are imported from outside the EU/EEA, all requirements regarding the import of medicinal products must be adhered to (particularly AMG §§72ff and Annex 21 of the EU GMP Guidelines). These includes, for example, holding a valid import license, meeting requirements for sampling and transport monitoring as well as ensuring EU-based analytical testing aligns with third country testing. In addition, specific requirements for sampling and transportation during import are laid down in EU GMP Annex 16. If there is no MRA (Mutal Recognition Agreement) or similar agreement with the corresponding third country, an EU analysis and, potentially an inspection in the third country are mandatory. Certification by the QP may only occur after physical import into the EU/EEA.

Further requirements: Additional information may be relevant for the release of the medicinal products e.g.:

• Ensuring the validation of processes and analytical methods
• Risk assessment of nitrosamines in the product
• Implementation of the ICH Q3D Guideline

Documentation on the above can either be obtained from the contracted parties involved or verified during audits.

What steps are involved in Batch Record Review during a release process?

Prior to market release, all requirements according to Section 16 of the German Ordinance on the Manufacture of Medicinal Products and Active Pharmaceutical Ingredients (§ 16 AMWHV) and Annex 16 of the EU GMP Guideline must be met. These include:

Review of Manufacturing/Testing records: A detailed review of all manufacturing and testing records is essential to confirm dossier- and GMP compliance of the finished medicinal product. Manufacturing batch records are compared with the authorised dossiers and process instructions to confirm the dossier-compliant manufacture of the medicinal product. Alternatively, compliance may be confirmed by check against approved manufacturing/testing instructions/specifications. The results of in-process controls are also considered. Regarding testing documentation, Certificates of Analysis (CoAs) for active substance(s), excipient(s) and the finished medicinal product are checked in particular to confirm compliance with specifications and overall quality. The manufacturing and testing protocols must also be signed by the respective responsible persons (Head of Manufacturing or Head of Quality Control). The QP determines the extent of the document review on a case-by-case basis.

Certificates of Compliance (CoC): The QP responsible for certifying the finished medicinal product batch may rely on confirmations (Certificates of Compliance, CoC) from other QPs and share defined responsibilities for manufacturing or import operations conducted at authorized sites in the EU defined in the relevant dossier. These CoCs are reviewed as part of the release process in accordance with EU GMP Annex 16 Annex I. The scope of a CoC must comply with the corresponding quality assurance agreement.

Review of transport documentation: A further component of the release process is the review of the transportation conditions of the bulk and finished product batches, particularly if the manufacturing steps occur at multiple sites.

Visual Inspection: One of the final steps in the release process is a “visual inspection” of the finished medicinal product. This involves random checks of the labelling on the primary and secondary packaging, including the package leaflet content, as well as the appearance and integrity of the medicinal product. For serialization-obligated products (in accordance with Article 54a (1) of Directive 2001/83/EC), security features e.g., the serialisation data (individual pack number (SN) and data matrix code) and the tamper-evident device, are also randomly checked.

Deviations / OOS: All deviations that occur during manufacturing and testing (e.g., OOS results) must be made available to the QP involved in the release process. All reports must be made accessible, if necessary, with determination of causes and measures and their implementation, so that the QP can carry out an assessment before batch release.

Retention samples: According to section 18 AMWHV and EU-GMP Annex 19, the QP must ensure that adequate reference and retained samples are stored.

Certification: If all relevant records and documentation reviews (including any deviation reports and OOS investigations) meet the requirements, the QP may proceed with batch certification. The QP confirms with signature that each batch das been manufactures and controlled in accordance with GMP and the marketing authorization/registration. Documentation of the certification is mandatory in accordance with the legal requirements (Section 17 AMWHV) in the batch register as well as in the batch certificate.

Transfer to the ready-for-sale stock (Batch release): After the QP certification, the batch can be transferred to saleable stock, usually by changing the status from “quarantine” to “released”.

Conclusion

The certification/batch release of medicinal products is a comprehensive process to ensure compliance with the approved dossier and GMP standards and thus the quality of the medicinal product. The Qualified Person plays a central role taking overall responsibility for the product quality and ensuring that all relevant information/documentation is available and thoroughly reviewed.

HWI offers comprehensive QP services and pharmaceutical consulting for placing medicinal products on the market. Our Qualified Persons are prepared to assume responsibility for you. Learn more about our services here: https://www.hwi-group.de/en/services/qp-services/qp-services.