quality agreements Archives - European Industrial Pharmacists Group (EIPG)

The drug shortage situation - EIPG's point of view


by Maurizio Battistini The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort Read more

EP’s draft position on Unitary SPC and SPC Regulation revision


by Giuliana Miglierini The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to Read more

Reactions to the proposed ban of PFAS


by Giuliana Miglierini A proposal to ban around 10,000 per- and polyfluoroalkyl substances (PFAS) was submitted in January 2023 to the European Chemicals Agency (ECHA) by authorities of Germany, Denmark, the Netherlands, Norway, and Sweden. The proposal was published on Read more

PIC/S new guidance documents for GDP inspectors

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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.


Key issues in technical due diligences

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by Giuliana Miglierini

Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due diligences, assessing the technological platforms and product portfolios to be acquired. A series of articles published in Outsourced Pharma discussed, under different perspectives, the main issues encountered in technical due diligences. We provide a summary of main messages to be kept in mind while facing this type of activity.

Technical due diligence of pharmaceutical products

The third millennium is being highly characterised by the closure of many M&A operations in the biopharma sector as a way to support the transfer of new technological platforms from their originators – usually an innovative start-up or spin-off company – to larger multinational companies. The latter are usually managing advanced clinical phases of development and regulatory procedures needed to achieve market authorisation in the territories of interest.

Furthermore, the acquisition of already marketed products often represents a way to renew the product portfolio or to enter new markets. Should this be the case, an article by Anthony Grenier suggests that a main target is represented by the understanding of how the products were maintained on the market by the seller company.

The restructuring of assets following acquisition may require the transfer of products manufacturing to sites of the acquiring company, or the possibility to use the services of a Contract Manufacturing Organisation (CMO). These are all issues that should enter the technical due diligence, that usually includes the exchange of information about the product, equipment, manufacturing, quality, and regulatory aspects of the deal.

The regulatory and quality perspectives

Regulatory due diligence takes into consideration the approval status of the interested products in target markets. Relevant documentation to be examined include the CMC dossier (Chemistry, Manufacturing, and Controls) and/or the Common Technical Document (CTD), and the current status of approval procedures undergoing, for example, at the FDA in the US or the European Medicines Agency in the EU. A possible issue mentioned by Anthony Grenier refers to the assessment and management of dossiers relative to unfamiliar markets, that may differ as for regulatory requirements and thus need the availability of dedicated internal resources or consultants. This type of considerations may impact also on the selection of CMOs; the transfer of older dossiers is also challenging, as they often do not reflect current requirements and standards and may require significant investments (including the request of additional studies) to support the submission of variations.

A visit to the facility manufacturing the product during the second round of bidding, in order to better understand issues related to the technology transfer, is also suggested. Technical documentation available to assessors should include copies of batch records and specifications for raw materials, active ingredients, and drug products. Analysis of the annual trends in manufacturing may be also useful, as for example a high number of rejected batches may indicate the need for a reformulation of the product.

From the quality perspective, the due diligence should also examine issues with supply or quality agreements, and the date of the last revision of documents. Examples of relevant documentation to be examined include process validation reports, change control lists, stability studies, inspection reports, etc.

The manufacturing perspective

In a second article, A. Grenier examined technical due diligence from the perspective of manufacturing, equipment and logistics.

The manufacturing process is key to ensure the proper availability of the product in the target markets, and it should be correctly transferred to the acquiring company or the CMO. To this instance, executed batch records are important to provide information on actual process parameters, processing times, and yields. Here again, process validation reports and master supply agreements provide information on the robustness of the processes and the steady supply of raw materials.

Consideration should also be paid to the transfer of any product-dedicated equipment involved in the manufacturing or packaging process, including its actual ownership. The time period for technology transfer should be long enough (at least 12 months) to ensure for the proper execution of all operations.

From the logistics point of view, it is important to understand the need to update printed components to reflect the new ownership of the product, a task that may result complex should it be marketed in many different countries and/or in many different dosage forms. Inventories of all raw materials, APIs, and packaging components should be also assessed, paying a particular attention to narcotic products for which specific production quotas may be present in some countries (e.g. the US).

Technical due diligence of entire facilities

M&A deals often involve the acquisition of one or more manufacturing facilities and other complex industrial assets. Anthony Grenier also examined the key factors impacting on this type of technical due diligence.

The “technical fit” between the two companies involved in the deal is a primary target for assessment, in order to evaluate the achievable level of integration and the existing gaps in experience to be filled. This may refer, for example, to the acquisition of a manufacturing plant for non-sterile products that would need to be converted for aseptic manufacturing: a goal that may require the building of new areas, thus the availability of enough space to host them. Experience of the staff is also highly valuable, as well as the successful introduction of new equipment.

Capacity of the plant should also be considered, neither in excess or defect with respect to the effective needs in order to avoid waste of resources or need of new investments. Experience of the seller company in CMO may be also relevant, as it may be used to fill some of the excess capacity. To this instance, the fields of specialisation and the availability of containment capability to avoid cross contamination are important parameters to be considered.

Compliance of the facility to regulatory requirements arising from the different target markets should also be assessed, as it impacts on the positive outcomes of inspections.

Highly complex technical due diligences

Technical due diligence becomes even more complex in the case of multi-site acquisitions. In this case, visits to assess specificities of the single facilities involved in the operation may be needed. The above mentioned parameters of technical fit, capacity and compliance should be always considered, and the take-at-home message from the A. Grenier is for the acquiring companies to “look for the weakest links that would prohibit them from bringing their product or technology to the sites to be acquired”. Capacity optimisation may be needed, for example.

The different steps of technical due diligence have been also examined in another article by Anne Ettner and Norbert Pöllinger published in Pharm. Ind.. They presented a mind map that clarifies the complexity of the items that should enter the due diligence process, and lists typical documents and questions that should be taken into consideration. Examples and case studies are also provided relative to the assessment of starting materials, the evaluation of the pharmaceutical formulations and that of the production process.