GMP Archives - European Industrial Pharmacists Group (EIPG)

The European Medicines Regulatory Network Data Standardisation Strategy


by Giuliana Miglierini The availability of interoperable data is a “must” to ensure the smooth sharing, use and re-use of data along the entire regulatory process. A new document - the European Medicines Regulatory Network Data Standardisation Strategy - has Read more

ICMRA published a Reflection paper on remote inspections


by Giuliana Miglierini Remote inspections have become a widely used approach since the last two years to ensure the oversight of the compliance of pharmaceutical productions to regulatory requirements, as the prolonged lockdown periods determined by the pandemic made very Read more

EMA’s Q&A on the integration of EudraGMDP and OMS


by Giuliana Miglierini A new step in the integration at the central level of data needed to manage regulatory procedures is going to be activated on 28 January 2022: starting from this date, member states’ national competent authorities (NCAs) shall Read more

ICMRA published a Reflection paper on remote inspections

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by Giuliana Miglierini

Remote inspections have become a widely used approach since the last two years to ensure the oversight of the compliance of pharmaceutical productions to regulatory requirements, as the prolonged lockdown periods determined by the pandemic made very difficult the maintenance of the regular schedule for on-site inspections.

A Reflection paper on the so gathered experience has been recently published by the International Coalition of Medicines Regulatory Authorities (ICMRA); the document addresses from the point of view of regulatory authorities the many issues encountered to establish appropriate modalities to interact at distance with the industrial counterparts by mean of digital technologies and suggests the best practices for the future. The analysis focused especially on remote GCP and GMP inspections.

The Reflection paper was drafted by a working group chaired by the UK MHRA and inclusive of representatives from the US FDA, EMA, Health Canada, Swiss-medic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO and Saudi FDA.

The lack of a uniform definitions and approaches

Each national competent authority adopted during the pandemic its own approach to remote inspections, evaluating this type of opportunity on a case-by-case basis, making use of established quality risk management principles and tools to reach their decision (par. 3 of the Reflection paper enlists the more widely used parameters for risk assessment and management).Among the factors entering this preliminary evaluation are the regulatory compliance history of the inspectee, the scope of the inspection (pre-approval, routine or for cause), and the inherent risk associated with the activities conducted by the site, the types of products and the need for the product.

The term used to identify the at distance interaction with the company to be inspected also assumed a quite wide variability; “distant assessment”, “remote evaluation”, “desktop assessment” or “remote assessment” are other frequent declinations used to define oversight procedures run by using digital technologies, both at the national and international level.

The choice of the specific term to identify this sort of practice depends upon many different factors, including the type of inspection and of the involved facilities, and the local national legal frameworks governing inspections as well as protection of personal data. The specific areas or sites to be included in the official review of activities, documents, facilities, records, etc. have proved also highly variable, as they may include not only the manufacturing site, but also investigator sites of a clinical trial, the sponsor’s and/or contract research organisation’s (CRO’s) facilities, or any other establishments deemed appropriate by the regulatory authority running the inspection.

Should the preliminary risk assessment had discouraged the possibility to conduct a remote inspection, the on-site inspections were usually postponed until the termination of lockdown measures in the interested countries. Hybrid or collaborative inspections represent another opportunity used to handle critical cases: the first ones involve the assessment or inspection to be conducted using a mix of remote and on-site activities, the second see two or more regulatory authorities collaborating to perform a conjunct inspection of a specific site.

According to the Reflection paper, it thus appears highly unlikely that a unique and fully harmonized approach to remote inspections in all scenarios might be developed for the future. “While the ICMRA group have found remote inspections an enabling tool to maintain at least a minimal regulatory oversight during the pandemic, it is not the view of the group that remote inspections would fully replace an on-site inspection programme”, states the document.

The main issues encountered

The possibility to conduct inspections, evaluations or assessments at a distance/virtually is based on the implicit availability of a robust IT and communication infrastructure; this has proved a fundamental requirement to smoothly share and review all the relevant documentation and ensure access from remote to systems and plants. Virtual tours of the manufacturing facilities are a typical example, for which the availability of solid “hardware and software that can provide an appropriate field of vision, clarity and stabilisation of the picture, while simultaneously facilitating conversation between the inspector and tour host” is essential to enable the real-time transmission of images and sounds captured by the in charge on-site staff by mean of smart devices or more advanced systems as smart-glasses.

In international inspections, the difference in time-zone and the availability of real-time, online translation services have also proved critical in many instances, especially if parallel sessions of discussion were needed. The possibility for inspectors to access on-line the relevant documentation requires the availability of the inspected company to provide credentials to enter in a read-only mode its proprietary document management systems and repositories. To this instance, confidentiality issues often led many companies to provide access to IT systems by mean of a specifically appointed member of the staff, in charge of accessing in real-time the systems and made available all the documentation as indicated by the inspectors.

The main areas of attention

The Reflection paper identifies four different areas for which remote assessment/inspection proved to be particularly useful during the pandemic period.

In the case of virtual tours, the indication coming from ICRMA experts is to limit the use of prerecorded video tours only in exceptional circumstances, and never for inspection of high-risk activities, as the inspector may not be in the right conditions to effectively verify all details needed to evaluate the suitability of the facility.

Direct access to documentation by inspectors is an expectation, electronically or otherwise, whether the inspection is on-site or remote”, states the Reflection paper. The alternative intervention of site staff may be acceptable, but it should not negatively impact the results of the assessment. Furthermore, this modality may also prove quite time consuming for both the inspector and the inspected company. ICRMA also supports the possibility for regulators to access documentation after the closure meeting, and upon the formal closure of the inspection, in order to facilitate the drafting of the report or to clarify a deficiency already raised.

GCP and GMP inspections

Specific issues for both GCP and GMP inspections are addressed in two dedicated chapters of ICRMA’s Reflection paper.

It should be noted that within the EU remote inspections at investigator sites are not considered to be feasible”, writes ICRMA. The motivation has to be found mainly in the need to avoid any further impact on the clinical sites during an health emergency like the pandemic, andin the issues posed by local frameworks for data protection. The Reflections paper provides a list of clinical areas not suitable for remote inspection.

As for GMP inspections, not all regulatory authorities adopted the same approach during the pandemic; in general terms, this sort of practice has been judged acceptable by ICRMA to handle emergency situations with restrictions to travels in place, but it cannot fully substitute onsite inspections of manufacturing sites. More specifically, the experience of the past two years shows that remote inspection proved unfeasible for sites requiring detailed observation, as those performing aseptic manufacturing or handling potent active ingredients with low Permitted Daily Exposure.


Automation of aseptic manufacturing

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by Giliana Miglierini

The pharmaceutical industry is often the last industrial sector to implement many new manufacturing and methodological procedures. One typical example is Lean production, those concepts were developed in the automotive industry well before their adoption in the pharmaceutical field. The same may also apply to automation: it appears time is now mature to see an increasing role of automated operations in the critical field of aseptic manufacturing, suggests an article by Jennifer Markarian on PharmTech.com.

The main added value of automation is represented by the possibility to greatly reduce the risk of contamination associated to the presence of human operators in cleanrooms. A goal of high significance for the production of biotech, advanced therapies, which are typically parenterally administered. Automation is already taking place in many downstream processes, for example for fill/finish operations, packaging or warehouse management.

The advantages of the automation of aseptic processes

The biggest challenges engineers face when designing isolated fill lines are fitting the design into a small, enclosed space; achieving good operator ergonomics; and ensuring all systems and penetrations are leak-tight and properly designed for cleanability and [hydrogen peroxide] sterilization,” said Joe Hoff, CEO of robotics manufacturer AST, interviewed by Jennifer Markarian.

The great attention to the development of the Contamination Control Strategy (CCS) – which represents the core of sterile manufacturing, as indicated by the new Annex 1 to GMPs – may benefit from the insertion of robots and other automation technologies within gloveless isolators and other types of closed systems. This passage aims to completely exclude the human presence from the cleanroom and is key to achieve a completely segregated manufacturing environment, thus maximising the reduction of potential risks of contamination.

The new approach supports the pharmaceutical industry also in overcoming the often observed reluctance to innovate manufacturing processes: automation is now widely and positively perceived by regulators, thus contributing to lowering the regulatory risks linked to the submission of variations to the CMC part of the authorisation dossiers. High costs for the transitions to automated manufacturing – that might include the re-design of the facilities and the need to revalidate the processes – still represent significant barriers to the diffusion of these innovative methodologies for pharmaceutical production.

The elimination of human intervention in aseptic process was also a requirement of FDA’s 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing and of the related report on Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach. According to Morningstar, for example, the FDA has recently granted approval for ADMA Biologics’ in-house aseptic fill-finish machine, an investment aimed to improve gross margins, consistency of supply, cycle times from inventory to production, and control of batch release.

Another advantage recalled by the PharmTech’s article is the availability of highly standardized robotics systems, thus enabling a great reduction of the time needed for setting up the new processes. The qualification of gloves’ use and cleaning procedures, for example, is no longer needed, impacting on another often highly critical step of manufacturing.

Easier training and higher reproducibility of operative tasks are other advantages offered by robots: machines do not need repeated training and testing for verification of the adherence to procedures, for example, thus greatly simplifying the qualification and validation steps required by GMPs. Nevertheless, training of human operators remains critical with respect to the availability of adequate knowledge to operate and control the automated systems, both from the mechanical and electronic point of view.

Possible examples of automation in sterile manufacturing

Robots are today able to perform a great number of complex, repetitive procedures with great precision, for example in the handling of different formats of vials and syringes. Automatic weighing stations are usually present within the isolator, so to weight empty and full vials in order to automatically adjust the filling process.

This may turn useful, for example, with respect to the production of small batches of advanced therapy medicinal products to be used in the field of precision medicine. Robots can also be automatically cleaned and decontaminated along with other contents of the isolator, simplifying the procedures that have to be run between different batches of production and according to the “Cleaning In Place” (CIP) and “Sterilisation In Place” (SIP) methodologies.

The design and mechanical characteristics of the robots (e.g. the use of brushless servomotors) make the process more smooth and reproducible, as mechanical movements are giving rise to a reduced number of particles.

Examples of gloveless fully sealed isolators inclusive of a robotic, GMP compliant arm were already presented in 2015 for the modular small-scale manufacturing of personalised, cytotoxic materials used for clinical trials.

Maintenance of the closed system may be also, at least partly, automated, for example by mean of haptic devices operated by remote to run the procedure the robotic arm needs to perform. Implementation of PAT tools and artificial intelligence algorithms offers opportunities for the continuous monitoring of the machinery, thus preventing malfunctioning and potential failures. The so gathered data may also prove very useful to run simulations of the process and optimization of the operative parameters. Artificial intelligence may be in place to run the automated monitoring and to detect defective finished products.

Automated filling machines allow for a high flexibility of batch’s size, from few hundreds of vials per hour up to some thousands. The transfer of containers along the different stations of the process is also automated. The implementation of this type of processes is usually associated with the use of pre-sterilised, single-use materials automatically inserted within the isolator (e.g. primary containers and closures, beta bags and disposal waste bags).

Automation may also refer to microbial monitoring and particle sampling operations to be run into cleanrooms, in line with the final goal to eliminate the need of human intervention.

Comparison of risks vs manual processes

A comparison of risks relative to various types of aseptic preparation processes typically run within a hospital pharmacy and performed, respectively, using a robot plus peristaltic pump or a manual process was published in 2019 in Pharm. Technol. in Hospital Pharmacy.

Production “on demand” of tailor-made preparations has been identified by authors as the more critical process, for which no significant difference in productivity is present between the manual and automated process. The robotic process proved to be superior for standardised preparations either from ready to use solutions or mixed cycles. A risk analysis run using the Failure Modes Effects and Criticality Analysis (FMECA) showed a lower level of associated risk.


Medical Cannabis in Europe

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by Giuliana Miglierini

Business based on medicinal products containing cannabis-derived substances has greatly developed in Europe in recent years, due to the many beneficial pharmacological properties offered by the plant Cannabis sativa. The global medical cannabis market is rapidly expanding (36% compound annual growth rate/CAGR 2017-2024), with Germany as the leading country (49,5% CAGR).

The medical use of cannabis in Europe refers to the EU Parliament’s resolution 2018/2775 of 13 February 2019, aimed to clearly and unambiguously distinguish between “medical cannabis” and “cannabis-based medicines”. The second ones have undergone clinical trials as all medicinal products and have been assessed by competent regulatory authorities to achieve approval. Only cannabis-based medicinal products should be considered for a safe and controlled medical use, suggests the Parliament resolution.

According to an article by Lipnik-Štangelj and Razinger (Arh Hig Rada Toksikol 2020;71:12-18), just one medicine characterised by a 10% concentration of cannabidiol (CBD, one of the main active components of cannabis) was centrally approved in 2019 by EMA for the therapy of intractable childhood epilepsy. Other medicinal products containing other types of cannabinoids have received approval through mutual recognition procedure or at the national level.

EU’s member states have not yet adopted a uniform approach on how to regulate the cultivation, manufacturing and use of medical cannabis; there is also a lack of uniform indications as for the modalities and contents of the labelling of cannabis-derived medicinal products. An extensive discussion of different legislative and regulatory frameworks relevant to the medical use of cannabis and cannabinoids have been addressed by a report published in 2018 by the European Monitoring Centre for Drugs and Drug Addiction.

The German approach

One of the first European countries to invest in medical cannabis has been Germany, where cultivation is allowed exclusively for medical purposes. A targeted Cannabis Agency (Cannabisagentur) was created in 2017 as a part of the local regulatory agency German Federal Institute for Drugs and Medical Devices (BfArM), in parallel with the coming into force of the Cannabis as Medicine Act.

The Agency has selected by a tender procedure three companies allowed to cultivate cannabis in Germany (Aphria RX GmbH, Aurora Produktions GmbH and Demecan GmbH), for a total production of approx. 2600 kg per year. BfArM started in July 2021 the state sale of medical cannabis from German cultivation, maintaining also open the possibility to import the plant for medical use.

The characteristics of the standardised cannabis extracts are described in a dedicated monograph of the German Pharmacopeia; the cultivation of the plant and the manufacturing of medical cannabis, which is a prescription drug, is also subject to the German narcotics law regulations (BtMG), to Good Agricultural and Collection Practices (GACP) and to Good Manufacturing Practices (GMP). German pharmacies can buy medical cannabis directly from the dedicated portal of the Cannabis Agency; a GMP/GDP-certified company is in charg of distribution. The price established by BfArM for pharmacies is 4,30 €/g.

The case in Greece

Greece also approved in 2018 a specific legislation on cannabis for medical use (Law 4523/2018, amending Law 4139/2013), providing the full reference framework for the cultivation, manufacturing, regulatory approval and distribution of cannabis-based medicinal products.

According to data by the Greek Ministries of Development and Investments and Rural Development and Food published in April 2020 by the Medical Cannabis Network, estimates of investments in the sector are reaching €1,68 billion and more than 8.000 employees.

The government aims to improve the attractiveness of Greece for cannabis cultivation and instalment of manufacturing plants – thanks to the favourable climatological and working conditions – as a way to support the expansion of the national economy. To this regard, possible competitors are Portugal, Malta or Cyprus, all countries characterised by similar favourable conditions.

Greece currently allows for the cultivation of cannabis with a THC content not exceeding 0,2%. A new law has passed in the Greek Parliament to regulate the production, export and distribution of final medical cannabis products with a THC content of more than 0,2%.

The new law is expected to create a special framework for cannabis businesses based in Greece and devoted to export only; their activities may be also subject to laws, regulations and GMP/GDP guidelines of the importing country.

Companies interested in establishing this sort of productions currently need to fulfil a wide set of conditions in order to receive permits for cultivation and authorisation by the Greek National Organisation for Medicines (EOF) to produce and market their products, which are classified as medicines. Criteria for authorisation are listed in the joint Ministerial Decision released in connection to the 2018 Law. The issuing of the permit by Greek authorities usually needs about three months time.

The common licence level allows for the initial establishment of a new manufacturing facility; the majority of companies which applied so far have received this type of licence (57/100). The second level of the licence refers to the authorisation to operation.

According to the experts interviewed by Medical Cannabis Network, current issues still to be solved include “establishing a clear definition of the type of greenhouses needed for a particular crop and the specific type of finished medicinal products that will eventually be allowed to circulate commercially”.

Malta, the QP for cannabis medicine production needs to be a pharmacist

Malta has issued in 2018 the Production of Cannabis for Medicinal and Research Purposes Act, the law governing the sector of medical cannabis for prescription.

The document provides detailed information on Quality & Stability of cannabis-based medical products (Appendix I), Security & Transportation (Appendix II) and Cultivation, Harvesting & Packaging (Appendix III).

Malta’s Medicines Authority is responsible for the evaluation of the technical and scientific documentation submitted by the applying companies, and for the issuing of the authorisations for import and wholesale distribution of cannabis-based products for medicinal use. Only finished products are allowed, they must also comply to the relevant legislation of the destination country.

The Maltese framework for the production of medical cannabis is characterised by the fact the Qualified Person (QP) responsible for the manufacturing plant has to be engaged by the license holder and must be a pharmacist registered with the Maltese Pharmacy Council and resident in Malta. This provision differs from the requirements outlined in Directive 2001/83/EC governing the manufacture and import of medicinal products for human use, transposed into the local Medicines Act and subsidiary legislation, where many other types of degrees (Pharmacy, Medicine, Veterinary, Chemistry, Pharmaceutical Chemistry and Technology, or Biology) are also considered.

Medical cannabis products licensed under the Medicines Act (Chapter 458 of the Laws of Malta) or manufactured under GMP can be sourced by licensed importers or wholesale distributors, provided the possession of the necessary approvals and permits. A Letter of Intent (LOI) from a Malta Enterprise is also needed to run operations related to medicinal cannabis production, analysis and research. The local regulatory agency can run inspections of the manufacturing facilities to verify their compliance to GxP; EU-GMP certification is needed prior to the starting of the manufacturing activities.

Research activities on medical cannabis is also supported through the Advanced Scientific Initiatives Directorate, in particular in the case of established organisations for scientific collaboration.

A pool of beneficial active ingredients

The plant Cannabis sativa contains a very rich pool of more than 480 compounds, among which are more than 100 cannabinoids. D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoid substances present in cannabis, the first one representing the main psychoactive and addictive constituent of the plant. On the other hand, CBD has no intoxicating or addictive properties. Many other cannabinoids possess an interesting pharmacological and therapeutic profile, and have been studied for possible use as neuroprotective agents (e.g. in case of anxiety disorders, depression, post-traumatic stress disorder), and for their effects as anti-emetics or on chronic pain (e.g. in cancer disease), inflammation, bacterial infections, etc.


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.