quality risk management Archives - European Industrial Pharmacists Group (EIPG)

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS


by Giuliana Miglierini The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents Read more

The transition towards EMA's new Digital Application Dataset Integration (DADI) user interface


by Giuliana Miglierini The Digital Application Dataset Integration (DADI) network project is aimed to replace the current PDF-based electronic applications forms (eAFs) used for regulatory submissions with new web-forms accessible through the DADI user interface. The European Medicines Agency (EMA) has Read more

IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics


by Giuliana Miglierini The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important Read more

Revision of the PIC/S GMP Guide: Annex 13 and Annex 16

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by Giuliana Miglierini

The entry into force of EU Regulation 536/2014 “Clinical trials”, at the end of January, resulted in the parallel updating of some international guidelines. In particular, a new version of the GMP Guide PE016 was published by PIC/S (Pharmaceutical Inspection Co-operation Scheme) on 1st February 2022. The revision included Annex 13 on the manufacturing of Investigational Medicinal Products (IMPs), and the new Annex 16 on the certification and batch release to be performed by Authorised Persons (AP) (click here to access all PIC/S guidance related to GMP). The revision of PIC/s guidelines is aimed to reflect the last changes occurred in the corresponding EMA documents, so to maintain the alignment between the two regulatory references (as established by the cooperation agreement between EMA and PIC/S). PIC/S has invited all non- EEA Participating Authorities and applicants to transpose the new Annexes 13 and 16 into their own GMP Guides.

The new Annex 16

Annex 16 represents a completely new addition to the PIC/S GMP guide; the EU Annex 16 (part of the EU GMP Guide) was initially considered to be too EU-specific and difficult to transpose for PIC/S purposes. Following a consultation in 2017, PIC/S Participating Authorities agreed to make an attempt to transpose EU Annex 16, as the adaptation may support a better harmonisation of GMP standards at the international level.

Annex 16 refers to both human and veterinary medicinal products which are subject to the PIC/S Participating Authority or are made for export. Furthermore, the Annex applies to investigational medicinal products for human use, “subject to any difference in the legal provisions and more specific guidance published by PIC/S Participating Authorities under national law”. With reference to imported medicinal products, each PIC/S Participating Authority may independently and voluntary decide whether to adopt the guidance as a legally-binding standard.

Certain types of medicinal products (e.g. blood and immunological products) are not addressed by the Annex, as they are regulated by national laws and fall under the competences of National authorities; to this instance, Annex 16 applies to the certification process performed by the AP and to the subsequent release of the batches.

The marketing authorisation holder (MAH) remains the sole responsible for the safety, quality and efficacy of the marketed products. Authorised Persons are required to check each single batch to verify compliance to national and GMP requirements, as well as to those detailed within the marketing authorisation (MA). After certification by the AP, batches of finished products can be transferred to saleable stock and/or export. Specific and documented agreements are needed should this require transfer to a site different from the certification’s one. Authorised Persons should be clearly identifiable, with reference to any quality defect leading to investigation or batch recall. APs certifying the release of the finished product are responsible for verifying the conditions of storage and transport for the batch and the sample, if sent separately, and of all testing required upon importation (including sampling, where needed).

A formal Quality Risk Management (QRM) process is required when sampling is performed at a manufacturing site located in another jurisdiction; Annex 16 provides detailed guidance on the elements to be considered in this exercise. Documentation of the continuous training received by the AP in charge of certification and batch release should be always available, with specific reference to the product type, production processes, technical advances and changes to GMP.

Annex 16 provides detailed guidance on how to conduct the process of certification of each batch of finished product, independently of the number of sites involved. With reference to specific manufacturing or control steps performed at different sites, their respective AP has to provide confirmation of the performed activities, sharing responsibilities with the AP in charge of the final batch release.

The certification process should take into consideration the entire supply chain of both the active substance and the finished product, including manufacturing sites of the starting and packaging materials. The AP responsible for certification should be able to access results of the audits performed at the sites involved, in order to check the consistency of all activities with those described in the MA and within GMPs. Audits run by third parties should reflect requirements set forth in Chapter 7 of the PIC/S GMP Guide.

In particular, suppliers of active substances should comply with GMP and GDP requirements relating to the supply of the active ingredient used to the finished product manufacturing. Excipients should also fulfil GMP requirements, and be possibly manufactured and supplied in accordance with the PI 045-1 guideline. Specific guidance may also apply for other types of products, i.e. biological active substances and medicinal products for human use or radiopharmaceuticals. Annex 16 provides templates for the confirmation letters to be used for the partial manufacturing of a medicinal product and for the content of Batch Certificates.

The revision of Annex 13

Annex 13 has been revised in order to reflect the contents of the new EU Regulation n. 536/2014 on clinical trials, which will replace EU Annex 13. PIC/S Annex 13 discusses the manufacturing of Investigational Medicinal Products (IMP), apart from the reconstitution phase, which is not considered to be part of the process. Provisions set forth by Annex 13 should be taken into consideration with reference to the re-labelling or re-packaging of IMPs and to the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products, occurring in hospitals, health centres or clinics and performed by pharmacists or other persons legally authorised in the country concerned.

All activities should refer to an appropriate Pharmaceutical Quality System to be in place, according to requirements set forth in Chapter 1 of Part 1 of the PIC/S GMP Guide.

 The characteristics of IMPs may intrinsically evolve along the development process, as new data become available that may require changes to, for example, the formulation or the dosage form. This has to be reflected into the respective product specifications and manufacturing instructions, that should also evolve in parallel and be fully traceable and documented. Annex 13 indicates that all deviations should be registered and investigated, and preventive and corrective actions put in place. The new Annex provides detailed guidance on the different items to be considered within the product specification file, as well as for the proper management of personnel, premises and equipment.

All the documentation generated during the clinical development phases should fulfil requirements specified by the PIC/S GMP Guide, Part I, Chapter 4. To this instance, relevant documentation includes specifications and instructions, orders, manufacturing formulae and processing instructions, packaging instructions and batch records. Detailed guidance is provided also for production, including packaging materials and manufacturing operations, the modification of comparator products, blinding operations, and the packaging and labelling of the IMP. Annex 13 also offers guidance on how to perform quality control and batch release, and how to address outsourced operations, complaints and recalls and or the destruction of batches of IMP products.


The new PIC/S guideline on data integrity

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by Giuliana Miglierini

The long waited new PIC/S guideline PI 041-1 has been finally released on July 1st; the document defines the “Good Practices for Data Management and Data Integrity in regulated GMP/GDP Environments”, and it represents the final evolution of the debate, after the 2nd draft published in August 2016 and the 3rd one of November 2018.
While maintaining the previous structure, comprehensive of 14 chapters for a total of 63 pages, some modifications occurred in the subchapters. The Pharmaceutical Inspection Co-operation Scheme (PIC/S) groups inspectors from more than 50 countries. PIC/S guidelines are specifically aimed to support the inspectors’ work, providing a harmonised approach to GMP/GDP inspections to manufacturing sites for APIs and medicinal products.

Data integrity is a fundamental aspect of inspections
The effectiveness of these inspection processes is determined by the reliability of the evidence provided to the inspector and ultimately the integrity of the underlying data. It is critical to the inspection process that inspectors can determine and fully rely on the accuracy and completeness of evidence and records presented to them”, states the Guideline’s Introduction.
This is even more true after the transformation impressed by the pandemic, resulting in a strong acceleration towards digitalisation of all activities. The huge amount of data produced every day during all aspects of the manufacturing and distribution of pharmaceutical products needs robust data management practices to be in place in order to provide adequate data policy, documentation, quality and security. According to the Guideline, all practices used by a manufacturer “should ensure that data is attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring, and available”. This means also that the same principles outlined by PIC/S may be used also to improve the quality of data used to prepare the registration dossier and to define control strategies and specifications for the API and drug product.
The guidance applies to on-site assessments, which are normally required for data verification and evidence of operational compliance with procedures. In the case of remote (desktop) inspections, as occurred for example during the pandemic period, its impact will be limited to an assessment of data governance systems. PIC/S also highlights that the guideline “is not intended to provide specific guidance for ‘for-cause’ inspections following detection of significant data integrity vulnerabilities where forensic expertise may be required”.

The impact on the entire PQS
PIC/S defines data Integrity as “the degree to which data are complete, consistent, accurate, trustworthy, and reliable and that these characteristics of the data are maintained throughout the data life cycle”.
This means that the principles expressed by the guideline should be considered with respect to the entire Pharmaceutical Quality System (and to the Quality System according to GDPs), both for electronic, paper-based and hybrid systems for data production, and fall under the full responsibility of the manufacturer or the distributor undergoing the inspection.
The new guidance will represent the baseline for inspectors to plan risk-based inspections relative to good data management practices and risk-based control strategies for data, and will help the industry to prepare to meet the expected quality for data integrity, providing guidance on the interpretation of existing GMP/GDP requirements relating to current industry data management practices without imposition of additional regulatory burden. PIC/S highlights that the new guidance is not mandatory or enforceable under the law, thus each manufacturer or distributor is free to voluntarily choose to follow its indications.

Principles for data governance
The establishment of a data governance system, even if not mandatory, according to PIC/S would support the company to coherently define its data integrity risk management activities. All passages typical of the data lifecycle should be considered, including generation, processing, reporting, checking, decision-making, storage and elimination of data at the end of the retention period.
“Data relating to a product or process may cross various boundaries within the lifecycle. This may include data transfer between paper-based and computerised systems, or between different organisational boundaries; both internal (e.g. between production, QC and QA) and external (e.g. between service providers or contract givers and acceptors)”, warns PIC/S.
Chapter 7 specifically discusses the Good document management practices (GdocPs) expected to be applied, that can be summarised by the acronyms ALCOA (Attributable, Legible, Contemporaneous, Original, Accurate) and ALCOA+ (the previous plus Complete, Consistent, Enduring and Available).
Data governance systems should take into consideration data ownership and the design, operation and monitoring of processes and systems. Controls should include both operational (e.g. procedures, training, routine, periodic surveillance, etc) and technical features (e,g, computerised system validation, qualification and control, automation or other technologies to provide control of data). The entire organisation should commit to the adoption of the new data culture, under a top-down approach starting from the Senior management and with evidence provided of communication of expectations to personnel at all levels. Sections 6 of the guideline provides some examples in this direction. The ICH Q9 principles on quality risk management should be used to guide the implementation of data governance systems and risk minimisation activities, under the responsibility of the Senior management. Efforts in this direction should always be commensurate with the risk to product quality, and balanced with other quality resource demands. In particular, the risk evaluation should consider the criticality of data and their associated risk; the guideline provides an outline of how to approach the evaluation of both these factors (paragraphs 5.4 and 5.5). Indication is also provided on how to assess the effectiveness of data integrity control measures (par. 5.6) during internal audit or other periodic review processes.
Chapter 8 addresses the specific issues to be considered with respect to data integrity for paperbased systems, while those related to computerised systems are discussed in Chapter 9. As many activities typical of the pharmaceutical lifecycle are normally outsourced to contract development & manufacturing organisations (i.e. API manufacturing, formulation, analytical controls, distribution, etc.), PIC/S also considered in the guideline the aspects impacting on the data integrity of the overall supply chain (Chapt. 10). “Initial and periodic re-qualification of supply chain partners and outsourced activities should include consideration of data integrity risks and appropriate control measures”, says the guideline.

The regulatory impact of data integrity
Recent years have seen the issuance of many deficiency letters due to problems with data integrity,. Approx. half (42, 49%) of the total 85 GMP warning letters issued by the FDA in 2018, for example, included a data integrity component.
The new PIC/S guideline provides a detailed cross-reference table linking requirements for data integrity to those referring to the other guidelines on GMPs/GDPs for medicinal products (Chapter 11). Guidance on the classification of deficiencies is also included in the document, in order to support consistency in reporting and classification of data integrity deficiencies. PIC/S notes that this part of the guidance “is not intended to affect the inspecting authority’s ability to act according to its internal policies or national regulatory frameworks”.
Deficiencies may refer to a significant risk for human or animal health, may be the result of fraud, misrepresentation or falsification of products or data, or of a bad practice, or may represent an opportunity for failure (without evidence of actual failure) due to absence of the required data control measures. They are classified according to their impact, as critical, major and other deficiencies.
Chapter 12 provides insight on how to plan for the remediation of data integrity failures, starting from the attention required to solve immediate issues and their associated risks. The guideline lists the elements to be included in the comprehensive investigation to be put in place by the manufacturer, as well as the corrective and preventive actions (CAPA) taken to address the data integrity vulnerabilities. A Glossary is also provided at the end of the guideline.