DIALOGUE: INDUSTRY MEETS AUTHORITY

   

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Two subjects were in the centre of attention at the third European GMP Conference in Heidelberg, Germany, in June: On the one hand discussions focused on the harmonisation of GMP requirements. On the other hand debates concentrated on the globalisation in the pharma supply chain and the associated current development of new GMP initiatives. Authority representatives from the EU and the US Food & Drug Administration (FDA) as well as industry professionals followed the invitation of the European Compliance Academy (ECA), the European QP Association and the University of Heidelberg.

Regulatory Developments in Europe

Dr Bernd Renger, Chairman of the European QP Association, gave a brief update covering the quite comprehensive GMP and regulatory developments in Europe.

  • After the heavy debates following the publication of the first concept paper for the revision of chapter 3 (Rooms and Equipment) of the EC GMP Guideline a new draft is expected still in 2009. This will identify those products in which the use of "dedicated self-contained facilities" is mandatory.
  • The expected revision of Annex 11 (Computerised Systems) will also trigger a revision of the chapter 4 (Documentation). Both final versions should be available in the 3rd quarter.
  • A proposed revision of chapter 5 (Production) supposed to reflect the obligations to only use active substances manufactured in accordance with GMP is actually on hold. This revision will also affect supplier qualification. Work is held pending until the new EU regulations about the combat on counterfeiting medicinal products are implemented.
  • Further, revisions are planned or come into operation for Annex 1 ("Manufacture of Sterile Medicinal Products"), in operation since March 2009 - with the exception of the topic "Capping" that will come into operation March 2010; Annex 2 (Biologics, only draft available); Annex 6 (Medicinal Gases, finalisation of revision was expected end of 2008); Annex 7 (Herbals), currently becoming effective; Annex 13 (Investigational Medicinal Products, draft available, public consultation ended Feb 2009); Annex 14 (Medicinal Products derived from Human Blood or Human Plasma, deadline for comments of a revised Draft ended July 2009).

Dr Renger expects that ICH Q 10 (Quality System) will become a new Annex of the EC GMP Guideline. Accordingly chapters 1 (Quality Management), 2 (Personnel) and 7 (Contract Manufacturing and Analysis) will have to be revised. A legal initiative to combat counterfeiting Medicinal Products has resulted in a proposal for an amendment to Directive 2001/83/EC that was issued by the European Commission in December 2008. This amendment will subsequently affect other Directives and Guidelines e.g. on Good Distribution Practice (GDP). A Concept Paper on GDP has already been issued in March 2009. A proposal for a Directive of the European Parliament and of the Council amending Directive 2001/82/EC and Directive 2001/83/EC in regards to variations of marketing authorisations has passed most European panels and will harmonise the variation process - independently whether the original marketing authorisation has been granted via a purely national procedure or via a harmonised Community procedure. But although member states will have to comply with this new Directive 18 months after it becomes effective, there are several grandfathering clauses, so full harmonisation will need several years.

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A revised reflection paper about QP Discretion was published in January 2009, but unfortunately this paper does not fully reflect the input provided during the 2007 Interested Parties Meeting (e.g. to the scope of deviations), as Dr Renger stated. This extension of scope is postponed until the new Variation Regulation has become effective. A Commission Directive on GMP for Excipients will not be published as initially announced as a positive list was considered not applicable. GMP conditions to be applied for excipients should be based on a Quality Risk Management process according to Annex 20 provided by the pharmaceutical manufacturer. However this risk based approach needs a revision of Directive 2001/83/EC.

FDA seeks better Communication

According to Thomas J. Arista from the Office of Regulatory Affairs in the FDA globalisation poses tremendous challenges for the USA. In 2007 there were

  • 835.000 manufacturers outside USA
  • Importation of 2 trillion US$ of products
  • Entry via 300 ports of entry

So there has to be another way around the regulatory "mountains", Arista said. A solution could be the Office of International Programs (OIP). The office has e.g. the responsibility to communicate with foreign governments and international organisations. This should give the opportunity to exchange better and more robust information from countries to enable FDA officials in the centres and at the borders to make better decisions about FDA-regulated products. OIP is also involved in managing formal arrangements with foreign governments, e.g. mutual recognition agreements, equivalence issues and confidentiality commitments. It facilitates international technical cooperation and assistance activities and capacity building across the Agency, stated Arista as important. Then Arista introduced the FDA concept to assist their global challenges: They have and will establish offices outside the US. There are current offices in China and India. Other offices will be soon in place and some are proposed.

The selection of offices is based e.g. considering the relationship that the FDA has with its counterpart regulatory authorities and the impact that an FDA presence will have on joint cooperative activities. The FDA collaborates with their regulatory counterparts to improve regulatory infrastructure, preventive controls and production practices. This includes a great variety of trainings. The FDA has recognised that it cannot inspect everything, but it does not need to inspect everything, Arista said. He expects to have mutual recognitions agreements, equivalence issues etc. in place earliest in five years. The final goal, though, is harmonised cGMPs.

In various sessions major stakeholders from authorities and industry discussed current developments to identify strategies for meeting the new challenges.

Quality by Design - Benefits and Implementation

The first session of the conference highlighted the quality by design and design space as parts of the 'philosophy' of a pharmaceutical development. Dr Josef Hofer, Director of Exdra and assistant lecturer for regulatory affairs at the University of Bonn, spoke about the benefit and implementation of QbD in reference to the current FDA belief that quality cannot be tested into products but should be build-in by design. The concept of QbD is to identify the critical quality attributes of a product resulting in a target product profile or SmPC. Taking into account the fact that process variability leads to product variability, we can achieve less process and ultimately less product variability, if we manage to monitor the parameters of the drug attributes. This leads us to the design space, where we can make the magic happen.

But what exactly is a design space? That's like a person's mind. No doubt it's free. But what about the conscience - isn't that a borderline? Still we must admit that a person's mind as well as a design space hides a great amount of opportunities. Design space is by definition the established multidimensional combination and interaction of material attributes and/or process parameters that have been demonstrated to provide assurance of quality. That looks a lot like a function of 'complex' variables or, as Dr Hofer referred to them, functional attributes with functional consequences. The advantage of the design space is that it provides a wider range, within which material attributes can vary - or as Dr Hofer clearly pointed out 'a highway instead of country roads'. The resulting business benefits of a designed space are significant: shortening time to market (which means shortening the time of approval), improved quality performance, reduced costs for development, manufacturing and control and, last but not least, the reduced regulatory compliance efforts, leading to more flexible regulatory environment, less regulatory oversight of minor changes, less documentation for variation, immediate change implementation. Dr Hofer also emphasised the fact that the design space would be difficult to use as an enforcement tool without an improved regulatory strategy, assessment and efficiency. At the end Dr Hofer summarised the 'desired state' for GMP in the 21st century.

Dr Michael Ulmschneider, a member of the PAT and analytical business process group at Hoffmann-La Roche in Basel, reported on promoting pharmaceutical excellence, advanced data analysis for process understanding, commenting on the same issue viewed from a different angle. That has a lot to do with the discussed theme above, because a successfully implemented QbD and an improved process understanding helps both industry and authority with running, controlling and monitoring processes at a well assessed science and risk-based level. So it could be as well described as a win-win situation. Process understanding is the basis for process control and assured end product quality. Using the methodology can help us understand what the number means rather than just what the number is. Dr Ulmschneider spoke about the use of analytical 'tools' (methodology) such as NIR, chemometrics and data mining for

  • improving knowledge of critical parameters for a better process understanding and more efficient analytics and manufacturing
  • learning from data to extract patterns for a better process control and faster action and
  • ongoing tracking of process performance data for higher confidence in the quality of batches and reducing costs. Learning from data leads to a better track: just follow the science and the drug will follow as well.

GMP Compliance and the Fight against Counterfeit and unsafe medicinal Products

The discussion theme of the second session was first introduced by Daniel Scheidegger, Managing Director of Genzyme Pharmaceuticals Switzerland and Chairman of the ECA. Mr Scheidegger reported on how to build a management system that implants an increasing number of regulatory requirements (GMP-related and Non-GMP related as HS&E, REACH etc.). The functional connection between number of regulatory requirements and compliance/ quality could pretty well be compared to a simple physiological process such as breathing. The recoil pressure (or in this case regulatory requirements) and compliance are in some cases inversely proportional. That simply means that a great 'recoil' force such as increasing number of regulations leads to a chance for decreased quality/compliance. But let's just start to consider the matter from the very beginning. How do regulations develop? The regulations follow a kind of 'a path of evolution', following the steps

1. prevention of things to happen again,
2. new trends and expectation: preventing things that may happen
3. competitive advantages, development of rules to build competitive advantages, harmonise markets and services
4. driver for: Where can we do more or better: internal SOPs vs. official regulations
5. regulations tend to become more detailed and come in higher frequencies.

The interests and goals of the regulations are to streamline processes and procedures and set levels for what is considered compliance, BUT level of detail in regulations, different perspective and field of regulation, different cultures, interpretation and enforcements in the global environment - all this can cause conflicts.

Daniel Scheidegger: "So what does that tell us?" This simply drives the compliance/quality to eventually and potentially crush under the burden of the increasing number of regulations and rules. General examples of regulations have been presented that showed such "crushes". The aim as with everything else in this world is the Aristotle's golden mean, the desirable middle between two extremes, one of excess and the other of deficiency. How can we achieve that? The first step of integration is, as Mr Scheidegger pointed out, understanding of the regulations (to understand something means to also be able to control it). Efficient integration of regulation in a business process requires, as he mentioned, the understanding of the regulation and an appropriate translation into the business system. To understand the regulations we must ask ourselves some questions and give some good answers. Questions, which concern the API and counterfeit are to be answered, as a discussion about counterfeit drugs leads us directly to one about the GMP compliance and of course the regulations. Then we come to the second step of the integration process, which is the understanding of processes and systems. By understanding the process and systems we can actually approach the idea of the desired state: a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight (Presentation, Ajaz S. Hussain, PhD Former Deputy Director, Office of Pharmaceutical Science, 2004 CDER, FDA). This leads to Genzyme´s Pharmaceutical Process Components.

Coding and Identification of pharmaceutical Products in Europe

Dr Stephan Schwarze, Head of Counterfeit Protection Management Bayer Schering Pharma AG and also member of WHO Impact's Technology Subgroup as well as of European Federation of Pharmaceutical Industries and Associations' (EFPIA) Anti-Counterfeiting ad hoc working group, spoke about a EFPIA' Project on Coding and Identification of pharmaceutical Products in Europe. He outlined the mandatory key elements for an efficient technological anti-counterfeiting strategy starting from the base line and moving upwards the pyramid:

1. guarantee the integrity of the original manufacturer's pack throughout the entire supply chain,
2. use of overt and covert features to authenticate products,
3. use of harmonised and standardised coding and identification systems for secondary packs of pharmaceuticals.

Each of these elements has the effect of making it harder for the counterfeits to get to the market. We need to enhance and harmonise the different identification systems of the EU member states so that we can gain a better control of the supply chain, which lead us to the main goal: improved patient safety and product quality. The system proposed by EFPIA, as Dr Schwarze explained, is intended to be an end-to-end product verification process at the point of dispensing.

He also pointed out that the most likely to be implemented and as well recommended from EFPIA Standard Coding is the 2D Matrix. Advantages of this system can be considered as follows: smallest symbol for a given quantity of information, robustness of the system, the usage of international syntax, the competitive cost. This system has been successfully used by IFAH for coding all animal products, which is definitely an advantage. There is a pilot project planned with 30-50 pharmacies in Sweden beginning in September 2009. The duration of the operational phase is expected with three to four months and approx. 100.000 coded packs to be dispensed. Afterwards the results will be evaluated.

Auditing in Non-EU and Non-US Sites - How to detect GMP Deficiencies and Counterfeit

Dr Jean-Denis Mallet from the International Committee Red Cross Pharmaceutics and Dr Heinrich Prinz, Senior Supervisor of Quality Control and Quality Assurance at CellMed, spoke about auditing in third countries, starting with the most important question: How can we detect GMP deficiencies and counterfeit as to insure patient safety and product quality. It's a difficult mission to accomplish as the culture there has its own peculiar way of doing things. Even if one goes there with the best intention in the world, he could easily be misunderstood.

The new FDA Validation Approach - How to establish the desired State

The last session of the conference brought up the following question: The new FDA Validation Approach - How to establish the desired state? Dr Thomas Schneppe, Head of Training Management at Bayer Health Care reported on Process Validation: General Principles and Practices. Dr Schneppe started his presentation by first pointing out what the GMP challenge was: The Product Quality Sigma is much higher than the direct Production Process Sigma. How can this gap be possibly bridged? In his opinion through the steps risk assessment, qualification and validation, monitoring, rework, reprocessing. He then focused on the various Q-ICH guidelines: ICH Q8 Pharmaceutical Development, ICH Q 9 Quality Risk Management and ICH Q 10 Pharmaceutical Quality System. Each of the guidelines can be represented as a Chart, which sums up the key elements so that one could get a better overview. ICH Q 10 or the Pharmaceutical System represents a kind of homeostatic system. So if we mess up with correctly implementing Q 8 and Q 9 we can't get Q 10 right.

Quality Risk Management

Quality risk management is integral to an effective pharmaceutical quality system. It can provide a proactive approach to identifying, scientifically evaluating and controlling potential risks to quality. It facilitates continual improvement of process performance and product quality throughout the product lifecycle. ICH Q 9 provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality ( ICH Q 10).

The idea of the Process Validation Lifecycle was also represented. That cycle includes scientifically sound Process Design practices, robust qualification and process verification. It links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during commercial production. There has been also a change in the validation process. The three batches Validation has been replaced by a so called three step approach: process design, process qualification, continued process verification.

Dr Christopher Burgess, Qualified Person and member of the QP Association Advisory Board, spoke about the process verification, process design and qualification. One of the ICH Q 10 objectives, as Dr Burgess pointed out, is to establish and maintain a state of control. The question is how we can do that? A continued process verification would assure continually that the process remains in a state of control during commercial manufacturing. To make that possible, key systems are being required such as a process performance and product quality monitoring system which
1. uses an established control strategy to facilitate timely feedback/feed forward and appropriate CAPA.
2. provides the tools for measurement and analysis of parameters and attributes identified in the control strategy, e.g., data management and statistical tools.
3. analyses parameters and attributes identified in the control strategy to verify continued operation within a state of control.
4. identifies sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation. So all in all it is a system that provides us with the answers of the good questions if we have the scientifical knowledge to understand what it says. It's not the number what it means.

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The Process of Validation is, as Dr Burgess mentioned, a journey and not three events (three batches). To sum it up: "Even if we see the end of the road as we are travelling, it certainly doesn't mean that we are already there!"

Author:
Yordanka Yordanova
... studies Pharmacy at the Goethe University in Frankfurt am Main, Germany.

Sven Pommeranz
CONCEPT HEIDELBERG

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