All operational procedures relevant to the acquisition, production, analysis, storage, import, export and marketing of medicinal products must be recorded in writing – normally in the form of instructions and records.
The minimum formal requirements for the documentation are: written form, accuracy, completeness, clarity, currency, approval and availability.
GMP-relevant documents include instruction documents, in which requirements are defined, and reporting documents, in which their implementation is recorded. Manufacturing instructions/protocols and test instructions/protocols are the core of GMP-relevant documentation, for which the management of manufacturing or quality control bears the responsibility under public law.
The aim of document management is to prepare information in such a way that it can be used for operational purposes. Document management systems (DMS) are usually used for this purpose. A distinction is made between classic, paper-based DMS, electronic DMS and mixed forms (hybrid DMS). Important requirements for document management systems concern access authorisation, change control, version control and availability.
The preparation and revision of documents should be carried out in accordance with established process instructions. In doing so, basic quality criteria have to be taken into account, which concern both formal and content-related aspects.
The control of the large number of documents in a pharmaceutical company requires a hierarchical structuring of the documentation system. A distinction is usually made between the strategic level, the operational level and the detailed level. In addition to the organisation system, the life cycle from creation to archiving also plays an important role. Documents must be handled according to de-fined requirements in each life cycle phase and at each hierarchical level. This also applies to the handling of document copies.
Compliance with good documentation practice requires that employees are adequately trained in its practical implementation and that the effectiveness of the training in practice is regularly reviewed.
GMP-relevant documentation must be stored for a certain period of time. An archiving strategy is required for this purpose. (Michael Hiob, PhD)
GMP-compliant documentation practices should ensure the traceability of all quality-relevant data and thus makes a significant contribution to drug and patient safety. The correct handling of prespecified documents and recorded data is also a prerequisite for data integrity. The company-specific rules with which this is to be achieved must be clearly and unambiguously defined in a work instruction (SOP). Central principles here are: “Every task is carried out exactly in accordance with current, approved procedures” and “If it is not documented it was not done.”
Good documentation practice not only applies to data collection, but must also be observed throughout the entire life cycle of a document, e.g., in the controlled distribution of copies and access-protected storage. Special attention must be paid to the handling of raw data (primary data). These contain original information that is important for quality assessment. They must therefore be carefully protected against alteration, mix-ups or loss. (Christine Oechslein, PhD; Cornelia Wawretschek)
Electronic document management systems (eDMS) are also gaining ground in the pharmaceutical industry. The selection of an eDMS suitable for GxP areas requires special care due to the special regulatory requirements: All GxP requirements for data integrity must also be met by these systems.
The requirements for an eDMS are quite different depending on the document types to be managed. Essentially, a distinction can be made between record documents, instructional documents and dynamic forms. Support for the management of files or dossiers requires more extensive functionalities in an eDMS.
Often, companies do not have a pure paper-based or electronic DMS, but rather hybrid forms. When introducing an eDMS, it is therefore necessary to check whether hybrid work steps also need to be support-ed, i.e. whether documents are to be printed from the eDMS, scanned and, if necessary, digitised again later.
The main objectives of introducing an eDMS should be to increase transparency and the ability to provide information within the company and to make processes more secure and accelerate them.
Whereas in the past IT systems were mostly installed at the customer's premises on the customer's IT infrastructure, today there is a trend toward cloud-based systems. The pharmaceutical industry has so far followed this trend only very cautiously for various reasons. The operation of a cloud-based system subject to validation requires the clarification of many additional questions and coordination with the cloud operator. There is also the question of whether to introduce a common eDMS for GxP and non-GxP areas or to use separate systems for these areas.
Typically, an eDMS is not an island. An eDMS is particularly economical when it is integrated into other software solutions of the company and receives data from them or makes it available there. During qualification/validation, particular attention must be paid to the interfaces of the eDMS to other IT systems and the resulting risks to data integrity. (Thilo Gukelberger)
The retention of data and documents in the active phase and archiving in the inactive phase of the data lifecycle must be regulated in detail on a company-specific basis in order to ensure data integrity and availability over the entire prescribed retention period.
The core element must be a list of what type of documents are archived on what data carriers and for what period of time (retention period).
Whether archiving is outsourced to external service providers or organised internally, and which archiving strategy is selected, depends on the volume of data, the required security levels, the space available and the expertise on hand.
There are no stipulations in the GMP regulations defining the assignment of responsibility for archiving. Each company must therefore define its own user roles and authorisations. This task is considerably more complex for archiving electronic data than for pure paper documentation.
Retention periods are specified in the GMP regulations only for certain batch-related documents. For all other documents and records, the time periods must be defined independently.
For both paper archives and electronic archiving systems, roles, authorisations and responsibilities must be clearly defined and documented, and the persons must be trained accordingly.
Archive rooms, archiving conditions and the procedures for archiving paper documents must be regulated and monitored in the same way as archiving strategies and security levels for electronic archiving.
Monitoring and maintenance procedures are particularly important for electronic archives in order to prevent data loss.
The destruction of files and deletion of electronic data at the end of the retention period must also be regulated in detail and be traceable. (Christine Oechslein, PhD)
EMA has further updated its Q&A on nitrosamine impurities. The latest version of 21 September 2021, includes an update of Question 10 “Which limits apply for nitrosamines in medicinal products?”
Therein, N-nitroso-varenicline, NNV, was newly added to the table of specific nitrosamines with a limit of 37.0 ng/day.
This value was derived using structure-activity-relationship (SAR) /read-across approach using the TD50 of N-nitroso-1,2,3,6-tetrahydropyridine as point of departure.
Please note: The Step 2-template for responses to the EMA to confirm that a nitrosamine has been detected was updated as well. It provides two options for alternative indication of limit values of newer nitrosamines not considered in the "Assessment report" (according to Article 5(3) of Regulation EC 726/2004) of the CHMP of June 2020:
The 28-page document provides rapid, development-related guidance to biosimilar and interchangeable biosimilar sponsors and other stakeholders on discrete issues. The Rev2-document includes newly finalised Q&As on the submission of a supplement to an approved application for a biosimilar. This covers the nature and type of information a sponsor should provide to support a post-approval manufacturing change for a licensed biosimilar or interchangeable biosimilar. The updated or new questions and answers are indicated by date.
After five years of drafting, PIC/S published the final version of a new guideline on data integrity. The document has already been applied in practice on a trial basis during this time and has been modified twice.
The resulting feedback was incorporated in the final version. Although the document is primarily addressed to inspectors, it is of course of interest to all pharmaceutical manufacturers. The document came into force on 1 July 2021.
With its remarkable 63 pages, the document covers all aspects that are to be considered when handling data in the GMP/GDP field. From basic principles, such as the ALCOA principle, to considerations for paper-based or computerised systems or the handling of so-called "findings" and potential risks, all areas are covered. Outsourcing activities and resulting actions such as audits, secure supply chain considerations or document verifications are discussed in a separate section. This also applies to necessary regulatory interventions: Possible "deficiencies" in data management are categorised and suggestions are made on how to address them. A comprehensive glossary concludes the document.
This document is a revision of the Guideline on good manufacturing practices: water for pharmaceutical use, which was previously published in the WHO Technical Report Series, No. 970, Annex 2, 2011. It considers water for pharmaceutical use (WPU) that is manufactured, stored, and distributed in bulk. Included are recommendations on various specifications for WPU, good practices for the quality management of water systems, water treatment systems (production), water storage and distribution systems, commissioning, qualification and validation, sampling and testing, and routine monitoring of water. Excluded from the document are the production, storage and use of water in quality control laboratories.
This guideline replaces the WHO Guidance on good data and record management practices (Annex 5, WHO Technical Report Series, No. 996, 2016). It includes "GxP for medical devices". In the interest of harmonisation, the document has been aligned to other existing DI guidances. In terms of content, the wheel has not been reinvented, but a clear structure and language speak for the document. Particularly noteworthy are the listed examples for quality risk management and data integrity assessments and the ten examples of good documentation practices in data integrity.