QUALITY MANAGEMENT AND DATA INTEGRITY IN API PRODUCTION
One of the basic prerequisites for the manufacturing of active pharmaceutical ingredients and medicinal products is the establishment of an effective quality management system. This is a legal requirement which has already been existing for many years. ICH Q7 and Part II of the EU Guidelines to Good Manufacturing Practice are the basis for the manufacture of API whereas ICH Q10 complements these requirements by specific aspects concerning the quality management system and regulations regarding responsibilities. Nevertheless, deficiencies in the quality management system are still the main problem the GMP inspectors note during their inspection rounds at the production sites of pharmaceutical companies and manufacturers of active pharmaceutical ingredients.
At the beginning of last year's APIC/ CEFIC Conference which took place at the end of November, Graeme McKilligan from UK's MHRA gave an overview of the expectations an inspector has on a functioning quality management system. Often, these expectations aren't met. In many times the problems occur already when implementing the system. Lack of personnel in the quality departments or inadequately trained personnel are the signs that the senior management is not aware of the central importance of a quality management system. In companies having these problems the inspector usually also finds violations of the GMP compliant handling of electronical systems and raw data. McKilligan's advice for improving a weak quality management system is to thoroughly and continuously train the personnel and raise senior management's awareness that a strong quality management system is not only an annoying regulatory requirement but an important contribution to the commercial success of the company.
Risk assessment plays an important role in quality assurance. This applies especially to the critical appraisal of supply chains which usually are global, span immense distances and are accordingly complex. Tom Buggy, DSM characterised typical supply chains using their imminent risks such as unclear responsibilities during the (interim) storage of products, lack of adequate documentation control, making traceability difficult, damage caused by improper handling and so on. A complete analysis of supply chains with a precise assessment of the respective risks provides the necessary transparency and is an important task of quality assurance. Apart from some relevant regulations and guidelines APIC's GDP "How to do" document offers orientation concerning minimum requirements for secure and transparent supply chains.
Berlin, Germany27/28 October 2021
24th APIC/CEFIC Global GMP & Regulatory API Conference - Part 2 - in Berlin or online
The intensified attention FDA pays to the topic data integrity can be seen in the numerous Warning Letters of the last years which list deficiencies concerning the handling of electronic systems and (raw) data. The discussions around the topic have been accordingly intense for some time now. But is this problem really a new one? Based on this central question Carmen Faba Tortosa from the Spanish Departamento de Inspección y Control de Medicamentos explained how GMP inspectors expect companies to handle data - and what they actually find. As a matter of fact the "Good Data and Record Management Practice" (GDRP) of many companies has been leaving much to be desired throughout the last years. This is the case although regulations concerning this topic have been existing for some time now (EU Guidelines to Good Manufacturing Practice, Part II Chapters 5+6, EU GMP Guidelines Annex 11, 21 CRF 210 Part 11, WHO Annex 5 etc.) and although the standards neither have changed substantially, nor have they become more stringent - not even in the recent documents of MHRA (GMP Data Integrity Guide) and EMA (Q&A on data integrity). Most deficiencies concern the following scenarios: Manufacturing of active pharmaceutical ingredients takes place in third countries, several activities are outsourced to sub-contractors and the supply chains are accordingly complex. Another risk factor are financial and economical problems increasing the probability of an insufficient data management.
Because of these scenarios Qualified Persons are often facing difficult decisions again and again, such as whether a batch can be certified with a clear conscience or not. "What keeps QPs awake at night from an API perspective" - this main question was the basis for Dick Bonners's lecture (United Kingdom) putting the focus on the ultimate responsibility of the Qualified Person of a pharmaceutical company concerning the used APIs. With the QP declaration concerning GMP compliance of the produced active pharmaceutical ingredient (according to Part II EU GMP Guideline) the Qualified Person also confirms the control over the supply chain, the suppliers and all other outsourced activities according to the principles of risk management. At this, situations may arise which call for a decision to be taken under enormous psychological pressure.
Dick Bonner illustrated this using the following example: The Qualified Person has just been told that the supplier of the active pharmaceutical ingredient used in the latest batch of medicinal products had his CEP revoked over six months ago. Delivery of the medicinal product is awaited urgently and the last vehicle which can get the product to the customer in time will be leaving the company's site in the next 30 minutes. There has never been any problem with this product in the past - so why not release the product now? Dick Bonner's advice in order to prevent such and similar nerve-wracking situations is the following: The better the relationship between the Qualified Person and the API manufacturer the easier the Qualified Person's job will be.
One of the most important quality criteria of active pharmaceutical ingredients is the impurity profile. Apart from the ICH Guidelines Q3A-C it have been especially the guidelines on elemental and mutagenic impurities Q3D and M7 that gave rise to intensive discussions in recent years. According to Diana van Riet-Nales from the Dutch Medicines Evaluation Board the deeper reason for the development of the M7 Guideline was the necessity to harmonise the relevant approaches between the regulatory authorities in the EU and the USA. Another reason was the fact that industry was dissatisfied with the way in which the EMA "Guideline on the Limits of Genotoxic Impurities" from the year 2006 was implemented in the individual EU member states. In the case of the Guideline ICH Q3D the situation is similar. There also was a need for harmonisation within the ICH regions. The challenge for industry as well as for the authorities lies within the strictly scientifically oriented approach in the risk assessment for active pharmaceutical ingredients and medicinal products required by ICH Q3D. This leads to divergent views between the assessors of the different EU member states which may cause delays in the approval procedure and in the worst case to arbitration proceedings. But this situation should improve with the growing experience with risk assessments on both sides. And this is necessary as according to ICH Q3D risk assessments will be required also for medicinal products already approved with effect from December 2017.
Risk assessment concerning elemental impurities has been part of the CEP procedure since August 2016 (it is not compulsory but highly recommended by EDQM). Hélène Bruguera, Head of the Certification Division of the EDQM in Strasbourg explained what CEP inspectors will concentrate on when looking at the risk assessment in the CEP dossier. A screening of batches alone is not sufficient. All dosage forms, possible sources of impurities (production equipment, tools and packaging materials), specifications, analytical procedures as well as information on the validation of these procedures must be described as far as they are known.
The compliance with GMP rules for the manufacture of active pharmaceutical ingredients has been a requirement since more than 16 years now. They are an important contribution to the patients' safety. But problems are still occurring again and again, at least in manufacturing sites in countries in the Far East. Brendan Cuddy, Committees & Inspections Department, EMA, London, explained the ranking in the frequency of statements of non-compliance during inspections in the period 2013-2015. The three most frequent deficiencies are insufficient data integrity (20%), deficiencies concerning facility, premises and equipment (16%), risk of contamination in the sterile manufacture (14%). This has far reaching consequences, including among others regulatory sanctions against the companies producing without GMP compliance and stricter legal requirements. Companies, importing active pharmaceutical ingredients from third countries have a higher responsibility than ever before. This responsibility is accompanied by a corresponding commercial risk should patients be harmed by quality deficiencies of the product.
Berlin, Germany26/27 October 2021
24th APIC/CEFIC Global GMP & Regulatory API Conference - Part 1 - in Berlin or online
On the one hand changes in the manufacture of active pharmaceutical ingredients are drivers for innovation and an increased efficiency but on the other hand they result in a substantial effort concerning the marketing authorisation documentation. Marieke van Dalen, Aspen Oss, Netherlands and board member of APIC explained by means of several examples how complicated change procedures can be in different countries. The simple replacement of a titration method by an HPLC analysis for the assay of an API is a change type 1B for the ASMF procedure in the EU, a change type 1A for the EU-CEP procedure, in the USA a PAS (Prior Approval Supplement) and in Japan a MCN, meaning a minor change. In addition fi ling dates and times for the handling vary depending on the region. In the case of generic active pharmaceutical ingredients this may actually lead to a situation in which the manufacturer of an API has to manufacture at the same time in the conventional way and according to the new (changed) procedure depending on the question whether the customer already has fi led the change with the regulatory authority or not.
Once again, the 19th APIC Conference in Barcelona has been an impressing example for the great importance of the exchange of information and opinions between representatives of the authorities and of industry. All participants still appreciate the valuable ideas for their daily work. This was demonstrated not only by the lively discussions in the plenum and during the parallel sessions, but also by the many discussions during breaks and during the joint dinner on the first conference day. The event has once again offered the perfect setting for this exchange of information.
Please note: The 20th European APIC Conference will take place in Berlin, Germany, from 25-27 October 2017. High-level representatives from international authorities and from industry will talk about the priorities and developments with regard to the supervision, manufacture and distribution of active pharmaceutical ingredients in Europe and in non-European countries.
Dr Gerhard Becker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and compliance topics.