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The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

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PIC/S new guidance documents for GDP inspectors

April 17, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

Two new guidance documents for GDP inspectors have been issued by the Pharmaceutical Inspection Cooperation Scheme (PIC/S) Expert Circle on GDP, and are available on the PIC/S’ website.

The ‘AideMemoire on the Inspection of Good Distribution Practice for Medicinal Products in the Supply Chain’ (PI 0441) and a ‘Questions & Answers (Q&A) document regarding the PIC/S GDP Guide’ (PS/INF 22/2017) both entered into force on 1 February 2023.

Main contents of the AideMemoire

The AideMemoire aims to support GDP inspectors in the understanding the process of GDP inspections. The document is expected to be used for training and planning of inspections. Its adoption is voluntary, as the PIC/S GDP Guide for inspections is a legally nonbinding document unless it has been declared a legal standard in the jurisdiction of a PIC/S Participating Authority. The AideMemoire addresses inspections in wholesale distribution sites of entities holding a wholesale distribution licence according to national legislation (i.e. including importing, exporting, holding, or supplying distributors), as well as manufacturers performing any distribution activities. GDP inspections should be thorough and conducted under normal operating conditions.

The AideMemoire is organised in the form of 10 tables that could be used by inspectors as check lists of items to be investigated during inspections of manufacturers and wholesale distributors.

The first table addresses general aspects of GDP inspections, such as the accuracy of the Licence/ application in detailing relevant activities and products. Lists of prescription only medicines (POM), sales without prescription (P), or General sales list/Over the counter (GSL) products are some examples, together all other possible items that may be handled by wholesales distributors, including medical gases, products requiring storage at low temperature and controlled drugs according to national laws.

Preliminary activities also include the review of previous inspections and the assessment of corrective/preventative actions (CAPAs) outlined in the company response. Change should also be verified, namely in the case of high risk operations that may affect the risk profile of the organisation.

Table 2 lists items referred to Quality management. Inspectors should check, for example, the availability of procedures and logs for change control and deviation management. Quality Risk Management (QRM) principles should have been applied to outsourced activities, leading to the definition of specific activities falling under GDP rules, approval, auditing of suppliers, etc. An appropriate procedure should be available also for activities referring to Management review and monitoring and QRM.

Issues referring to personnel are discussed in table 3. An organisation chart and job descriptions should be available, the latter reflecting also key responsibilities and indication of Designated Responsible Persons. Inspectors should verify GDP training received by personnel, also with reference to specific aspects such as falsified medicines or temperaturesensitive products. Availability of a regular GDP training programme and training records should be checked. Personnel should have received specific training in SOPs relevant to their role, to be adequately assessed and documented. These should also include aspects relative to health, hygiene and clothing requirements.

The check list referred to Premises and Equipment is detailed in table 4. It includes among others items reflecting segregation requirements (e.g. identification, design and management of segregation areas) for hazardous or radioactive products, falsified medicines, products not authorised for the approved market, expired products, etc.

Cleaning and pest control procedures are also addressed in this section, as well as temperature and environmental controls and the appropriate monitoring of fridge or cold storage conditions. As for the equipment, inspectors should verify planned maintenance and calibration and their respective records. Alarms should also be checked, as well as computerised systems including validation, security and access restrictions. Appropriate qualification and validation procedures should be in place for all relevant equipment according to QRM principles, and risk assessment should be also available.

Table 5 lists all items referring to documentation management, including procedures and records. The qualification and approval of suppliers and customers according to QRM principles is addressed in Table 6, discussing Operations. This section also addresses the availability of goods receipts to be checked against purchase orders, including details of the temperature conditions during transportation and checks at receipt for products with special storage requirements or nonconforming products. Stock rotation according to the First Expiry First Out principle (FEFO) should be verified by inspectors, among items referred to storage. Aspects referring to the security of the premises also fall under this section, as well as the destruction of expired/ obsolete goods. Inspectors should address also picking operations, supply notes and records and procedures for import/export.

Table 7 refers to the management of complaints, returns, suspected falsified medical products and recalls, which should all be handled according to relevant procedures. Requirements and documentation to be verified for outsourced activities are listed in table 8. These include for example the availability of quality agreements, and contracts including clear responsibilities and audits schedules.

Procedures, plans and records referring to selfinspections are listed in table 9. Items to be verified by GDP inspectors include among others the selection of auditors, their training and independence, CAPAs implementation and verification. The last table addresses issues relative to transportation, including planning, outsourcing, temperature monitoring, GDP training of drivers, etc.

Q&As on PIC/S GDP Guide (PE 0111)

The second document published by PIC/S consists in a list of Questions & Answers specifically referred to the PIC/S GDP Guide (PE 0111). Contents are organised in the form of a table detailing the relevant chapter number and title, paragraph number, question and answer. The latter also make reference to other paragraphs of the GDP Guide to be considered. The sequence of topics is similar to that of the previously examined guidance document for inspectors.

Questions referred to Chapter 1 address issues referred to Quality management and Quality system, outsourced activities, management review and monitoring. Effectiveness of the QS, for example, may be measured by inspectors with reference to deviations and CAPA analysis or to the impact of QRM functions. Frequency of periodic review and responsibilities for ensuring GDP compliance of outsourced activities are also addressed.

Personnel and definition of responsibilities, including key positions and delegation, are detailed in Chapter 2, while Q&As referred to Premises and Equipment go deeper in contents of Chapter 3 (i.e. including the definition of “acceptable temperature limits” and use of Mean Kinetic Temperature for monitoring).

The following chapters and related Q&As address the proper management of Documentation (Ch. 4) and Operations (Ch. 5). The later details some aspects of suppliers and customers qualification, storage, picking. The management of complaints, returns and particular categories of medicinal products refers to Chapter 6. As for outsourced activities (Ch. 7), Q&As addresses onsite auditing, while selfinspections are treated in Chapter 8. Q&As referred to Transportation (Ch. 9), for example, refer to national legislations as for the need for the transportation company to hold a wholesaler licence.


ECA’s guide to compliant equipment design

March 31, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The legislative evolution of the last decades emphasised requirements for equipment used in pharmaceutical productions. This is even more true with the entry into force of the new Annex 1 to the GMPs, characterised by many new requirements impacting on different manufacturing processes (i.e. production of water for injection, sterilisation, Form-Fill-Seal and Blow-Fill-Seal technologies, single use systems, lyophilisation, etc.).

Each pharmaceutical process requires the careful design of the needed equipment in order to provide the expected efficiency and performance. Furthermore, some equipment may be used for different industrial applications (e.g. pharmaceutical, cosmetic or food), thus needing a fine tuning to reflect relevant requirements. In pharmaceutical manufacturing, a further step of complexity may be represented by the need to handle highly potent active pharmaceutical ingredients, requiring isolators to segregate production, etc.

To facilitate the correct design of equipment compliant to GMPs, a new guidance document has been published by the ECA Foundation. The document was initially drafted in German by a task force of experts in pharmaceutical technology and engineering and published by Concept Heidelberg, and it has now been translated in English

Elements relevant to reach compliance

The first part of the document discusses general requirements that should always be part of the design of GMP-compliant equipment. Four different points of attention are listed: the equipment must not adversely affect the product quality, it must be easy to clean, it must comply with applicable technical rules, and it must be fit for its intended use.

As for the first point, “The question is rather what is tolerable without adversely affecting the product quality”, states the guidance. Avoidance of contamination and cross-contamination are the main goals of cleaning activities, both for sterile and non-sterile medicinal products. There are several issues to be taken in mind from this perspective, including the presence of endotoxins, sealing points, the efficiency of cleaning-in-place (CIP) processes, or the presence of unreachable dead leg areas. According to the guidance, the 3D/6D rule for the prevention of dead legs in water systems often used for specification would not always be correctly applied, due to some confusion in terminology. Official GMPs are also deemed “very vague”, as they are not drafted by engineers and apply to an extremely wide range of different equipment and processes. “Consequently, the question is, which technical rules have to be followed or where the actual state of the art can be looked up”, says the document. Many different references are possible, from pharmacopeia monographs and regulatory guidelines, to ISO standards, and other documents published by international professional bodies.

Qualification and calibration of equipment should always be targeted to the specific product, as it is an essential in proving compliance to the intended use. Regulatory compliance of submitted documentation is not less important, and it greatly impacts on change control and implementation of new productive technologies.

Risk analysis (RA) is the tool introduced in 2005 by ICH Q9 to evaluate all items which may impact on the design of productive processes and related equipment. There is no standard methodology to run risk analysis, the choice depends on the process/product under assessment. According to the guidance, RA can be performed both from the perspective of the product and the equipment, the latter being also considered a GMP risk analysis.

Design and choice of materials

Materials (and coating materials where relevant) used to build pharmaceutical equipment should be completely inert. Pharmaceutical equipment must comply with the EC Directive on Machinery 2006/42/EC and DIN EN ISO 14159. The ECA guidance discusses material selection (plastics or stainless steel); hygienic system design is also addressed by many different guidelines, e.g. those published by the European Hygienic Engineering and Design Group (EHEDG). An important item to consider is service life considerations for the materials used (EHEDG Document 32), as well as their chemical-physical characteristics and materials pairing.

Particularly critical are process contact surfaces, as they may impact product quality. Establishment of specific requirements is thus needed. The guidance focuses its attention on austenitic stainless steels (i.e. CrNiMo steels 1.4404 and 1.4435). The main elements to be assessed are the risk of corrosion, the risk of contamination of the product or process medium and the cleanability of the metallic surface. Topography, morphology and energy level are the main characteristics to be used to describe surfaces, addressing respectively the geometric shape, chemical composition and energy required per unit area to increase the size of the surface. The guidance provides a detailed discussion of all different aspects of surface treatment methods, and the hygienic design of open and closed equipment. Other sections discuss the optimal design of pipework and fittings, connections, welding and seam control. Detailed information is also provided on equipment of electrical engineering, measurement and control technology, as well as the process control technology (PCT) measurement and control functions.

A highly critical area within a pharmaceutical facility are cleanrooms, for which the design of the equipment and the choice of materials is even more stringent. Elements to be considered include stability/statics as concerns dynamic loads, smoothness of the floor, tightness of external façades and of enclosing surfaces of cleanrooms. Smooth nonporous surfaces are required, together with avoidance of molecular contamination, resistance to the intended cleaning or disinfection agents and the cleaning procedure, simple and tight integration of various fittings, efficient and rapid implementation of subsequent functional and technical changes. The ECA guidance document goes deeper into relevant requirements for all elements that are part of the design of a compliant cleanroom.

Documentation and automation

User requirement specifications (URS) are the key document to demonstrate equipment is fit for the intended use, as stated by GMP Annex 15 (2015). The ECA guidance suggests translating the URS in a technical version to be submitted to the potential equipment supplier, so to ensure the design would reflect product and quality-relevant requirements, being thus GMP compliant.

The management of documentation along the design life cycle of a new piece of equipment is also taken into consideration, with the different construction phases identified according to Good engineering practices (GEP): conceptual design, basic design/engineering, and detailed design/engineering.

The extensive use of data to monitor and document pharmaceutical manufacturing process represents another area of great attention. Requirements relevant to the design of validated computerised systems, data protection and data integrity must be kept in mind. ECA’s experts highlight the need to carefully delimitate areas subject to validation and their extention, particularly with reference to automated systems. Differences between qualification and validation of automated systems are also addressed, including equipment that might either be defined as “computerised” or “automated” system. Regulatory reference for validation is GAMP 5, while qualification refers to Annex 15.