The pharmaceutical industry in
Many of these practices and case studies of how manufacturers are implementing QbD were discussed at a series of meetings and workshops sponsored by EU regulators and pharmaceutical trade groups over the past few months to encourage more companies to incorporate QbD into their operations.
It appears that there has been quicker adoption – and less ambiguity – surrounding the International Conference on Harmonization Q9 risk assessment guideline. The guideline is helping inspectorates, especially smaller ones, decide which firms to inspect first.
Yet despite progress made in harmonizing inspections under the auspices of ICH, some pharmaceutical companies are experiencing “overinspections,” and the problem is getting worse as many regulators, perhaps feeling vulnerable by the recent scares in the pharmaceutical supply chain, are starting to demand their own inspections, even if they have mutual recognition agreements with the EU.
QbD changing EMEA’s inspectional focus
The European Medicines Agency in November 2005 adopted the ICH Q8 guideline on pharmaceutical development, which encompasses QbD, effective May 2006. Afterward, the ICH Q9 guideline on quality risk management and the ICH Q10 guideline on the pharmaceutical quality system were adopted, the three guidelines together supporting the new ICH paradigm.
EMEA officials acknowledged that the ICH trio has influenced inspectors’ focus going forward.
David Cockburn, head of manufacturing and quality compliance for EMEA, explained Sept. 29 at a meeting hosted in
He further noted that “change control will be a point of interest in identifying and dealing with excursions from the design space.”
Inspectors will also be looking at a firm’s quality management system including training of staff and outsourced activities, calibration of process analytical technology measurement tools, and supplier qualification programs.
Cockburn further noted that as a result of QbD, “we foresee more pre-authorization inspections initially. These may be triggered by assessors who may wish to explore something in more depth, to assess the practical implementation of QbD, and to ensure that the quality system is sufficiently robust and properly implemented to deal properly with the new flexibility afforded it.”
He also said that “ICH Q10 applies throughout the lifecycle of the product. The application of quality system concepts to development activities is critical to the successful commercial manufacture of the product. In principle development studies could be inspected although GMP does not apply. However, GMP inspectors do not foresee routine (ICH Q10) inspections and do not foresee Q10 certification.”
In term of ICH Q9, Cockburn noted that “the principles of ICH Q9 are being increasingly applied within the GMP and quality systems of manufacturers. The correct use of these principles and relevant tools is expected and encouraged.”
However, Cockburn said that one unresolved issue is the relationship between in-house assessors and outside inspectors.
“More discussion is needed to clarify the roles of inspector and assessor in the light of these new ICH approaches to quality and to ensure that the aims of the new vision for quality discussed at ICH in 2003 are achieved.”
Decentralized procedure not amenable to QbD
Yet while regulators may be looking for more QbD in submissions, one EU pharmaceutical industry member said that firms may be more reluctant to embrace QbD in their manufacturing operations because of the fragmented nature of the process for submitting new applications under the decentralized procedure and the differing requirements governing QbD among various member states.
Only about two percent of product submissions are new molecular entities submitted to EMEA for centralized review whereas the overwhelming majority of applications, 97 percent, are submitted at the decentralized level to one or more member states.
Yet firms that submit to EMEA have much more clear-cut guidance from the agency on how to use QbD and PAT in their applications.
EMEA reports that eight marketing authorization applications approved have used QbD and PAT elements.
QbD submission numbers misleading
Yet Jean-Louis Robert, of
He contends that many marketing authorization applications he has reviewed already have some QbD and PAT-like elements, especially in the drug development phase. They are just not identified as QbD submissions.
With the EU “Development Pharmaceutics” guideline, which went into effect in the early 1990s, manufacturers have already been identifying critical quality attributes or critical quality parameters in their marketing authorization applications.
What is new with the QbD approach is that pharmaceutical development is performed in a more systematic way, using more formal risk management tools, conducting design of experiments, using a more scientific understanding of both process and product, and applying a life cycle approach to development.
Companies can now apply for opportunities like design space, real-time release testing, and the use modern technology such as near-infrared spectroscopy to monitor a process by determining the blending end point rather than having a fixed blending time.
Robert noted that, “I try to avoid the use of the term QbD as much as possible. We have to avoid that it becomes degraded to a slogan.”
Encouraging industry with mock submissions
To help manufacturers gain a better understanding of the necessary information to support QbD, PDA sponsored a workshop in
The four mock submissions included QbD principles applied to terminally sterilized products and lyophilized injectable drug products as well as to small molecule and monoclonal antibody drug substances.
The papers were meant to improve the understanding and interpretation of how QbD concepts can be applied to different types of drug products.
In a PDA report of the meeting, Brian Withers, director of CMC for Abbott and co-chair of EFPIA’s product development and CMC ad hoc group, explained that “EFPIA compiled first the ‘Examplain’ Mock P2 discussion paper, which gave the ability to see a case study illustrating some QbD concepts including proposals for flexible regulatory approaches. It was felt that injectables would benefit from being discussed in a separate paper. Initially only a terminally sterilized formulation was targeted but it was clear that a lyophilized product was sufficiently different to warrant an independent document that would concentrate on this process and its implications when QbD concepts were applied.”
Withers said that the papers “are to be used to stimulate discussion. They do not give a recipe or generic solutions. Once understood, they can be used as a starting point for thinking about applying QbD to real products.”
Graham Cook, senior director of process knowledge and QbD for Wyeth, told “The Gold Sheet” that “much of the focus of QbD has been on solid dosage forms, it’s nice to see QbD applied to, for example, lyophilization and of course the EFPIA Mock P2 injectable products.”
Cook said that the meeting generated “lots of questions and requests for clarification and deeper understanding suggest that the efforts of professional organizations, such as PDA, putting on workshops such as this one, together with activities by the trade associations in conjunction with the regulatory agencies both regionally and globally, through ICH IWG, are very valuable in helping with implementation of this new quality paradigm.”
EMEA/EFPIA workshop explores case studies
A week later, on Sept. 28-29, EFPIA and the EMEA held a workshop in
Industry representatives and regulators also discussed the challenges in implementing this new paradigm and how it can work for specific types of drugs, processes and manufacturers.
The companies presented their QbD experiences during closed “individual” sessions with EMEA the first day, including four small molecule experiences and two biotech product experiences.
There was generic feedback from the six presentations on the second day. The meeting was attended by 120 regulators and 130 industry representatives.
The case studies were as follows:
Merck Sharp and Dohme: The firm was investigating the integrated application of a QbD development approach across the chemical and formulation process.
Merck’s use of a FMEA risk assessment for drug product process development focused on understanding dissolution behavior and bioavailability.
Pfizer: The company was using continuous quality verification and continuous processing as an approach to process validation. The main topics discussed in this case study were traditional validation versus continuous verification approaches, the indirect monitoring of critical quality attributes and the relationship between real-time release testing and CQV, and the definition of a batch for a continuous process.
Eli Lilly: In this study, Eli Lilly examined the use of in-line near-infrared spectroscopy to monitor segregation of a pharmaceutical powder blend in a tablet press. The case study examined real time powder uniformity monitoring during compression using a non-contact NIR probe. Company officials found that the NIR technique allowed for rapid and non-destructive content uniformity assessment. The conclusion from the case study was that the “in line NIR method provides for an additional tool in the QbD/PAT tool box.”
Astra Zeneca: The company explored the use of in vitro and in vivo data to define both a design space and a control strategy. The main topics discussed in the case study were the use of risk assessment and prior knowledge to focus investigations toward understanding the impact of product and process variables on in vivo performance.
Wyeth: The company explored the use of QbD in deriving critical quality attributes, critical process parameters and a design space using quality risk assessment and design of experiments on a scale-down model of the manufacturing process of a novel therapeutic protein.
The main topics explored were how to feed back large scale experience into scale-down models, how a company can show that all factors have been considered during development, and how the risk ranking process was conducted in the area of setting thresholds and scoring.
Amgen In this case study the company used process development and product characterization studies to set specifications for a novel recombinant monoclonal antibody.
There was consensus in the company that movement within a unit operation design space is not a change requiring regulatory oversight, and that clarity from regulators regarding how to make complex changes within multiple design spaces is needed. And there was also discussion on what a S2.5 process validation and evaluation looks like in a post-approval QbD environment.
Company officials learned from the case study that:
· a design space and control strategy may be linked to safety and efficacy;
· that risk assessment and prior knowledge drive the development program, which may result in different approaches for different products;
· NIR spectroscopy is a potential and suitable tool for controlling process and product quality;
· there is a need for industry to continue to define, justify and focus on critical quality attributes and critical process parameters, and;
· there is a need to provide a rationale for non-critical attributes and parameters.
Key lessons learned from case studies
Georges France of Wyeth, who was one of the facilitators at the London workshop, reported at the PDA-EMEA meeting in Berlin on Oct. 14 that one of the findings that emerged from all six case studies was that “implementing Q8, Q9, Q10 and QbD was definitely a challenge and if not a revolution more of a transformation.”
There was also acknowledgment that implementation of QbD concepts “represents a cultural change for both industry and regulators and is a bridge between development and manufacturing and a bridge between assessors and inspectors.”
In terms of the design space scale up,
He also emphasized the need for an introduction in the application file explaining the rationale behind the development strategy, including the overall control strategy.
PDA advances best practices guide
And on another front, PDA is also aiming to encourage more QbD submissions through the use of a best practices guide under a new initiative called the Paradigm Change in Manufacturing Operations, or PCMO.
From PDA’s perspective, there is still an unmet need in terms of how to implement the ICH guidelines. The draft centers around four main themes: life cycle approach, quality systems, process management and quality risk management.
Lothar Hartmann of F. Hoffman-LaRoche in
The ISPE initiative “is aimed at supporting ICH concepts from a regulatory point of view whereas the PCMO comes more from an industry point of view. What does this mean for manufacturing and how to organize this whole aspect in providing products. That is the main difference.”
PDA is communicating with PQLI officials on how the two groups can work together “and not have a competition from two different associations but more or less a paradigm change for the entire company; one from a regulatory and the other from a manufacturing point of view.”
Hartmann noted, “We want to address the change from process management to process verification. We have new concepts with validation. We want to talk about how to increase process robustness and statistical methods and what is a reasonable CAPA for our industry. How can we apply such things to a daily business? The last piece is risk management.”
From the PCMO initiative, PDA plans to publish a series of technical reports and white papers for members. PDA plans to release these papers early in 2010.
Less ambiguity and quicker uptake of ICH Q9
There is less ambiguity surrounding the implementation of the ICH Q9 risk management guideline, which has been adopted without much fanfare by both regulators and industry.
Vjaceslavs Krauklis, a GMP inspector for
The ICH Q9 guideline addresses the various stages of the quality risk management process, including risk assessment, control, communication and review.
The guide also provides a general overview of some of the primary tools that may be used in quality risk management. Among those described are failure modes and effects analysis (FMEA), fault tree analysis, and hazard analysis and critical control points.
The description of each of the various tools is followed by a brief discussion of their existing and potential areas of use in the pharmaceutical industry.
Another section covers the overall integration of quality risk management into industry and agency operations.
Krauklis explained that the risk ranking tool considers the type of inspection such as whether it is a full site part time or product oriented; the complexity of the site in terms of the size and the variety of the facility; the complexity of the manufacturing process such as the type of technology used and the process control applied; the complexity of the product and its therapeutic significance and the patient exposure.
There are two inspectors for 29 manufacturing sites. The state allows for 110 inspector days on site per year and preparation and reporting time is not included.
The inspectorate conducts routine GMP inspections, pre-authorization inspections, third country inspections, centralized inspections and inspections with the European Directorate for the Quality of Medicines and the World Health Organization.
Other duties of a small inspectorate include API inspections, routine GDP inspections, pre-authorization inspections, rapid alerts, Eudra GMP, EMEA GMP, Pharmaceutical Inspection Cooperation Scheme and WHO inspections.
In 2007 they issued 40 inspection reports, then it fell to 30 in 2008 and then it was 10 in 2009.
The risks of being small are that inspectors often “work as firemen” because of the high risk of non-comprehensive outcomes due to inspectors being responsible for many tasks.
Also, he explained that because of the small number of inspectors, specialization in a particular area is not possible; there is a limited number of competent and experienced employees, there is the risk of conflict of interest; and there is the risk of not maintaining an inspector’s competence in accordance with technical and scientific progress.
The advantages of being small are a straightforward and simple communication process inside the inspectorate, “strong and stable cooperation between inspectors and assessors,” there is small industry and manufacturing presence which require limited technology, and inspectors have strong knowledge of every site.
Training an integral piece of risk management
With the publication of the ICH Q9 quality risk management guideline, the European Commission, the EU member states and EMEA decided that training activities in risk management principles should also involve regulators as well as the pharmaceutical industry.
The guide incorporating these principles is called “Guideline on Training and Qualification of GMP Inspectors” and it went into effect in December 2008. The guide covers the requirements for basic training, in-service training, continuous training and time spent on training.
Tor Graberg, the chief pharmaceutical inspector and head of the inspection unit for
Graberg noted that “sometimes you get surprised with varying interpretations of regulatory authorities. For me training is our number one job. The person who says ‘I know it all,’ I have never met that person. Because it’s an ongoing process inside the agencies and industry. In some certain areas you are the trainee and you are the schoolboy. It could be [difficult] for some people to realize this.”
“Once a person is certified, training is ongoing. In my mind you have to have a recertification scheme as well. Every second year we have a re-examination and a re-evaluation training.”
Graberg said that the appeal of the training guide has broadened outside the EU to international health authorities.
The
These plans were discussed at the fourth meeting of PIC/S in April.
“Risk management is a way forward to make sure we’re doing the right thing in the inspectorate and that you have the right philosophy in your company.”
More coordination needed for inspections
Despite progress made in harmonizing inspectional requirements worldwide under the ICH umbrella, more work needs to be done in this area to eliminate the trend towards “overinspections,” said one manufacturer.
Thomas Barthel of Boehringer Ingelheim of
In 2008, he hosted seven authority inspections, in 2009 this grew to 13. This corresponds with a dramatic increase in the number of days to complete an inspection; from a total of 14 days in 2007 to 51 days in 2009.
These inspections are for either routine GMP compliance inspections, new products, new facilities, renewal of product submissions, new program, risky products such as sterile or biotech products and cancellation of additional quality control testing.
This growth in inspections has been driven in three waves, he said.
Barthel explained that “the first wave” countries, such as the
The increase is also being fueled by what he calls “second wave” countries, such as
The safeguard clause means that a regulator, while agreeing to the “equivalence” of the other regulator’s inspection, is allowed to perform their own inspections for a specific area they don’t feel is adequately covered by the others. This includes biologics in
The increase in requests for inspections is also coming from “third-wave” countries that have started to implement stricter GMP controls, he said. These countries include
In terms of unique inspectional requirements, in
In the
In the
Barthel recommend that to overcome this problem of overinspections, more countries should exchange inspection reports to share information and honor MRAs that are in place.
He said that half of all inspections “are geared towards GMP questions. This information should be shared. No exchange of information between authorities makes life very complicated.”
– Joanne S. Eglovitch (j.eglovitch@elsevier.com)
This article first appeared in The Gold Sheet on Dec 18, 2009.
