20/21 November 2019
GMP News No. 925: Current GMP and Regulatory Developments on Active Pharmaceutical Ingredients
Current GMP and Regulatory Developments on
In his opening speech, APIC's President, Matt Moran, talked about
the various challenges faced by the European API industry today. Against the
background of European legislation and Far Eastern competition, the
association's activities assume additional significance. The focussed
dialogue with the authorities, in which the urgent questions and problems of
API manufacturers are addressed, represents one important element of APIC's
The series of presentations was started by Dr Katrin Nodop from the
European registration authority EMEA. Against the background of current
GMP requirements on API manufacture as laid down in the EC-GMP Guide and the
corresponding EC Directives, Dr Nodop explained which situations can trigger
the inspection of an API manufacturing plant by the competent supervisory
authority. Two important documents published by EMEA describe these
inspection-triggering situations as well as the expectations of audits,
including those contracted out to external specialists (Third-Party Audits):
the "Inspection Triggers" Guideline and the "Questions and Answers on
Audits" document. Due to global ways of distribution, inspectors have to pay
special attention to the transport chain between the manufacturing site of
the API and the place where it is used or processed. Dr Nodop emphasised
that the only valid means to check the criterion of GMP-compliant API
manufacture and to prove this compliance to the supervisory authority is a
GMP audit conducted (or - in the case of a Third-Party Audit - initiated) by
the manufacturing authorisation holder (MAH). It is not enough to refer to a
"self-assessment" audit conducted by the API manufacturer.
A comprehensive overview on the life cycle model of process validation in API manufacture as seen by the American supervisory and registration authority was presented by Grace McNally, FDA. Each of the 4 phases of the life cycle of process validation focuses on one activity - design, confirm, monitor, assess - and is characterised by the corresponding increase in information on process variables, analytical data, product specifications and process deviations as well as optimisation opportunities according to trend analyses. In any case, the FDA expects an API manufacturer to acquire sufficient knowledge about the manufacturing process based on a comprehensive database prior to marketing the product. Here, the early development stage of a process plays an important role. The FDA considers later attempts to adapt and optimise the process after placing the product on the market to be critical.
The implementation of "Quality by Design" from the FDA's viewpoint was the subject of the presentation given by Dr Moheb Nasr, FDA. This principle has crucial benefits for both the API manufacturer and the authority, said Dr Nasr. This became clear in his comparison between the hitherto practised method and the "desired state" reached through consequent implementation of the "Quality by Design" principle. This approach includes systematic, multivariate experiments in the early development stage (the "Design Space"), a robust manufacturing process controlled by process-analytical technologies (PAT) as well as a risk-based control strategies. Ideally, this enables a "real-time release" (RTR) of batches without quarantine period. A cost-benefit analysis shows that, whereas at first an increase in investments has to be expected, the desired state will result in significant cost reduction, among others due to the fact that process changes within the design space can be made without major regulatory efforts. Dr Nasr emphasised that the FDA welcomes any attempts to implement this principle in the development of new products and that it is open and willing to co-operate constructively with the companies that decide to adopt this course.
EDQM Director Dr Agnès Artiges gave a lecture on new developments regarding the CEP procedure and explained the EDQM's programme to assess APIs destined for the European market. One important pillar of the CEP procedure is the inspection programme developed by EDQM. Within the framework of this programme, an audit is conducted on the site of the API manufacturer to check whether the production technology found there actually corresponds to the CEP dossier. The most frequent complaints during such audits are inconsistencies in documentation and records as well as deficiencies in quality management, material management and process equipment. In the meantime, about 90 manufacturing sites in 22 different countries - among them China, India, Mexico and Canada - were audited. In 12 cases the CEP was suspended due to critical deviations; in only 2 cases the CEP could be restored after re-inspection. Another pillar of the surveillance of API quality is the network of Official Medicines Control Laboratories (OMCLs). There are already approximately 85 of these public and independent laboratories in over 35 countries, which are involved in a large number of projects and e.g. take part in collaborative testing for monograph and reference substances or analyse counterfeits. The threat constituted by a growing number of counterfeited APIs led the EDQM to bring an initiative into being that includes a specific EDQM-OMCL procedure and is also supported by APIC. This procedure is meant to regulate the intensive information exchange between the EDQM, the competent national OMCL and the API manufacturer; at the same time the conclusion of a confidentiality agreement signed by EDQM and OMCL protects the know-how of the manufacturer. According to Dr Artiges, this procedure will make an important contribution to defending the European Market from inferior substances in the near future.
The industrial perspective on GMP- and registration-related topics was illustrated by 9 representatives from the pharmaceutical and API industry during the plenary sessions.
Jan Moors from Pharmaceutical BV, the Netherlands, talked about the experiences of a generics manufacturer with the new EU legislation on active ingredients. After the legislation had come into force, many of the contracts with suppliers had to be revised and adapted with regard to the new GMP requirements on APIs. With the help of specific examples he illustrated the difficulty to access audit reports of third-country manufacturers when medicinal products are imported. Another case he mentioned was the problem to procure an API after the long-term supplier's CEP was suspended as the negative result of an EDQM inspection.
How the principles of risk management described in ICH Q9 have to be applied to an API manufacturing site, was explained by Barbara Lani from Bracco International, Manno, Switzerland. In her lecture she presented the factors determining the quality of a production process and used a large number of examples to show in which way they were analysed from a risk-based point of view and which control mechanisms were established afterwards.
In his presentation Gerry Migliaccio, Vice President Global Quality Operations Pfizer, New York, USA, dealt with statements in the ICH Q10 Guideline on pharmaceutical quality systems. Gerry Migliaccio is also Head of the Expert Working Group elaborating the ICH Q10 Guide. He stressed that the "ICH Quality Trio" constituted by ICH Q8, Q9 and Q10 should not be looked upon as separate documents; their benefits rather come to the fore when they are seen in combination and, when applied consequently, lead to a more effective risk management and higher regulatory flexibility, since there are less changes and variations in the process of which the authority has to be notified.
Dr John Berridge from Pfizer, Ramsgate, UK, described in detail the principles of pharmaceutical development laid down in the ICH Q8 Guideline. With the help of examples he made it clear how systematic data analysis can help to define a multidimensional space, the "Design Space", within which the product possesses the desired quality. In the end, the quality that was "built into" the process design right from the start results in continual improvement of the process. He gave an impressive example of this: the reduction of a waste solvent quantity to the three-hundredth part of the original volume.
In another lecture on "Quality by Design" from an industry viewpoint, Wendy Mavroudakis from Johnson & Johnson Pharmaceutical Research and Development, Titusville, USA, outlined how this principle can reduce regulatory efforts. With the help of concrete examples she demonstrated what a scientifically sound risk-based marketing dossier can look like that includes the crucial facts relevant to process understanding and therefore equally represents an advantage for the Regulatory Affairs department of the pharmaceutical company and for the reviewers on the part of the authority.
Examples of the implementation of Process-Analytical Technology (PAT) were presented by Conor McSweeney from Pfizer, Cork, Ireland. Critical process steps and parameters, like e.g. the end point of a chemical reaction, crystallisation or particle size, are monitored online by means of suitable analytical technologies, and thereby, an optimisation, a greater understanding and, ultimately, a better control of the process is achieved.
The consequences of the EU Directive, which came into force not long ago, for an Indian API manufacturer were the lecture subject of Dr Nandkumar Chodankar from Sekhsaria Chemicals, Mumbai, India. In a historical excursion, he described the development of the Indian pharmaceutical and API industry and showed how it rapidly caught up with European GMP standards in recent years. A quickly growing number of audits by authorities, like EDQM and FDA, and by European customers, led many companies to rethink. The Indian API industry is experiencing a boom; however, only 300 of the approximately 11,000 registered units are large-scale firms and account for 70% of the market share.
In his lecture, Dr Jan Smeets illuminated the significance of impurities in APIs in connection with creating the marketing dossier. Stricter requirements in the European Pharmacopoeia regarding impurities and their identification force API manufacturers more and more frequently to procure reference standards for a large number of impurities, which often takes a lot of time and money. Dr Smeets strongly advocated a revision of the corresponding pharmacopoeial chapters and the concept that the registration authorities should focus more on safety-relevant facts than merely on analytical results of the batches when judging a dossier.
Dr Mike James presented EFPIA's proposals for a revision of the Variations Regulation in the EU, which had been forwarded to the European Commission at the end of September 2006. Currently, notifiable changes involve a high regulatory burden. The increasing tendency to hand in such notifications under the Centralised System is tying up more and more resources both on the part of the industry and on the part of the authorities. EFPIA's suggestion for the revision of the Variations Regulation aims at a different way of classifying or grouping the variations ("related and grouped variations") and propagates a procedure for sharing out the tasks for medicinal products registered on a national level.
The event was rounded off by 8 parallel sessions, during which the aspects mentioned in the lectures could be consolidated and discussed in detail. The following topics were offered, from which the conference participants could choose two:
On the whole, this conference was characterised by a great willingness to
discuss matters and an openness on all sides. Thus, this event has once more
made a contribution to the mutual understanding and reinforced co-operation
between the European API industry and the supervisory and registration
authorities. The changes in the framework conditions have set other things
in motion, and the challenges for all parties concerned have grown.
The 10th APIC Conference in October this year will take this development
up. 7 representatives from supervisory authorities (e.g. EMEA, FDA,
EDQM) and 11 experts from the
pharmaceutical industry have already confirmed to give a lecture. On the joint
GMP and Regulatory Affairs day, every participant can choose from 2 out
of 8 parallel sessions. The ECA supports this unique event for the API
industry. ECA members receive a 5% discount on the regular registration
fee. Please follow the link to view the programme and