Case study: Validation projects in China

This case study details the experiences of Pharmadule Morimatsu in guiding leading Chinese manufacturers through facility investment projects aimed at achieving compliance with Chinese, US and EU Good Manufacturing Practice (cGMP) requirements.

Chinese manufacturers have therefore become among the first in the world to fully embrace the work procedures outlined in ICH Q8, Q9 and Q10. Implementing these guidelines in large organisations would be a challenge with any global market.

However, the Chinese manufacturing environment offers both advantages and cultural challengeswhen managing change.

Introduction: Changing Chinese GMP environment

Between 1997 and 2000 Pharmadule built a number of pharmaceutical manufacturing facilities in China on behalf of domestic manufacturers, as well as multinational pharmaceutical companies, including Eli Lilly and AstraZeneca. These multinationals required world-class GMP compliance and validation services equivalents to the highest standards that operate today.

The manufacturing facilities delivered to Chinese manufacturers were also capable of complying with international GMP requirements. However, it was evident at the time of construction thatChinese GMP regulatory requirements were immature in comparison with EMA and FDA regulations and guidelines.

In 2011, all of this changed when China launched its new GMP regulations, which elevated manufacturing quality requirements to a level equivalent with international cGMPs. This change coincided with a refocusing of Pharmadule strategy towards the Chinese market.

Since then, Pharmadule has carried out a series of Validation, Quality Management Systems (QMS), cGMP improvement and design projects in China. Compared with projects undertaken during the late 1990s, these recent assignments required Pharmadule to consider a number of significant changes in the Chinese marketplace when designing a modernized approach for project execution in China that is also applicable to other emerging markets.

Chinese manufacturing characteristics

One major difference is that while European and American pharma manufacturers typically have a QA/QC-force amounting to up to 40 per cent of the production staff, the Chinese companies encountered had very small QA/QC departments, mainly focusing on QC and batch release testing. Quality was typically tested and validated into the products and processes. Interestingly, the immaturity of these QA and QC practices were partially helpful in speeding the transition to modern validation planning and execution.

The main reason for this is that there is a light ‘baggage’ burden of existing practice. In contrast to the multinational pharmaceutical companies Pharmadule has worked with over the past 25 years, Chinese companies do not have bureaucratic and over-compliant Quality Management Systems and validation frameworks. Rather, they could be characterized as non-compliant with EU or US regulations.

This is of course a concern when it comes to the current level of Quality Assurance expertise. However, Chinese clients were very open to embracing new ideas and knowledge, allowing them to evolve faster than any other market where Pharmadule has worked in the past.

Chinese organisations offered little resistance to change, provided they understood the benefits and the details of the new approaches. Consequently, implementation of new business processes could be much faster than has been typical in Europe or North America.

Changes that would take half a decade or more to fully implement in a multi-national pharmaceutical company in the EU or the US have been accomplished in China in a matter of months.

Process validation standards

When a new facility is being built, it provides the manufacturer an opportunity to completely change the approach to Quality Assurance and validation.

Recent assignments completed by Pharmadule in the Chinese market have seamlessly integrated the philosophies described by international regulators in ICH Q8: Pharmaceutical Development, Q9: Quality Risk Managementand Q10: Pharmaceutical Quality Systemswith the overall concept of Process Validation.

Process Validation guidelines are described in the FDA’s Process Validation Guidance(2010)and ASTM E2500: Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment.

The Pharmadule team also took other international standards into consideration in order to create a state-of-the-art Validation Master Plan (VMP). This VMP governs the entire product and process life cycle (Figure1) and is used to manage all of the phases of an investment project.

The main steps of this plan combine to form a control strategy that allows an unbroken chain of traceable verifications all the way from the product attributes (e.g., shelf life) via Quality by Design activities in the Process Design and scale-up, through design and qualification, all the way to process validation. This level of traceability is rare even among established international companies.

Implementing new QA cultures and new paradigms for process validation were not easy in some cases. The Pharmadule team encountered a number of obstacles, some obvious, some less so. But there have also been circumstances in China that enabled the shift to take place faster and more easily.

Chinese culture

It was a positive surprise to find that the degree of process understanding was very high among engineers, comparable to western expectations or even exceeding them. This can probably be attributed to the effectiveness of the Chinese education system.

However, this process understanding was rarely fully leveraged into the process design and the GMP documentation. With the right tools and training, process understanding could easily be transcribed into Critical Quality Attributes, Critical Process Parameters and ultimately risk-based control strategies. Defining these boundaries and limits for the process in Quality by Design work was both efficient and accurate.

Quality by Design (QbD) also facilitated, and eliminated unnecessary aspects of Technology Transfer, since Process Design departments, Operations and QA worked closely together. One impediment that could slow down changes is the lack of any challenge to authority that is inherent within traditional Chinese culture. Corporate culture in China rarely encourages coworkers to take risks and explore new solutions. In fact, many companies punish employees that take risks and fail, with public shaming and fines. This places a cap on the capability for innovative thinking and creative solutions.

It is, therefore, important to note that, in contrast to the engineers, operators in the facilities do not have the same level of training as their western counterparts and will not take own initiatives. They normally only speak Chinese and will, for the reasons stated above, follow the SOPs they are given very rigorously. When training operators, this must be taken into account.

Turning QbD into specification

Turning process understanding and QbD into a User Requirement Specification (URS) is a challenge that is not unique to Chinese manufacturers. International companies also regularly fail in this area. The sheer number of process engineers, support from management, detailed instructions and a flexible approach to change, allowed rewriting of the URS to enable traceability of critical parameters and aspects. Revamping the URS has consequently been easier than expected. This is a key activity in providing the foundation both for procurement and for the rest of the validation activities, which is why the new draft Annex 15 to the EU GMP guidelines specifically highlights the URS as part of the validation process.

In China there is an additional challenge that increases the importance of URSs.Traditional Chinese vendor management pushes all the responsibility for design, commissioning and qualification — up until at least Operational Qualification — on the equipment vendors. Audits and contract management have not been common practices. On the contrary, maintaining good relationships between business parties is considered so important that these bonds sometimes supersede written agreements.

If the supplier is to play a big part in the qualification, as is the intention in ASTM E2500, etc., then suppliers must initially undergo audits to ensure that they are able to provide risk-based documentation. Next, each supplier must obtain a URS that allows preparation of risk-based documentation, finallythere must be communication between supplier and client during the design phase to ensure an understanding and alignment with the risk-based principles needed. This has been a key area for attention from the validation team.

Process performance qualification challenges

The state of the QMS became even more important as each project moved closer to the next step in the life cycle, Process Validation (referred to as Process Performance Qualification in the latest FDA guidelines). This represents both a practical and cultural change for the Chinese pharma manufacturing industry.

QMS processes have traditionally focused on how to achieve the product specification in accordance with GMP and Pharmacopeia through extensive end testing of products and intermediates. Process Validation has frequently consisted of three batches, tested in accordance with the product specification as defined in the registration file. There is no scientific basis for limiting the number of validation batches to three, and while this practice may still be acceptable in the EU, there is a movement in the US towards a more science-based approach.

Extended testing (i.e. extra tests outside the product specification to obtain an even more robust verification) that has become expected practice in Europe and North America has not been the normal practice in China.

One of the main advantages of risk and science-based validation is that it provides a control strategy based on residual risk after process design and equipment qualification. This control strategy is an input for the Design of Experiments for process validation batches that provides a scientific rationale for the number of batches and defines the extended testing needed. Control strategies also help define appropriate programmes for continuous process performance monitoring (i.e. Continued Process Verification). To achieve this goal there is a need to implement a Pharmaceutical Quality System including a number of elements that traditionally have not been prioritized.

Change Management, Deviation Management, Supplier Management, Continual Improvements and Product Quality Reviews are examples of activities that need to be implemented not just in the documentation, but also in practice. This has represented a major cultural change for most Chinese pharma manufacturers.

CFDA Enforcement

Currently the industry in China is waiting to see how the Chinese Food and Drug Administration (CFDA) will interpret and enforce the new GMPs from 2011. This may seem to be long overdue since now over three years have passed since the regulations were promulgated, but the CFDA recognized that the new requirements were setting completely new standards for the industry and gave a grace period until January 2014.

During recent months, Chinese authorities have inspected a large number of sterile and aseptic manufacturers. It has been recognized that while central CFDA has been very strict in their interpretation, China is an enormous country and it will take time for the new interpretations to trickle down to the provincial CFDA inspectorates. Therefore, the industry is still awaiting the outcome of local inspections. This gridlock will probably remain in place well into 2015. If the CFDA is enforcing the new GMP as vigorously as has been announced, there will surely be an increasing demand for new equipment and facilities, but the main demand will be new well-documented and improved Quality Management Systems.

Many of the leading manufacturers are not waiting for the results of the first real CFDA new GMP audits, but have instead chosen to aim for compliance with EU GMPs for their current project portfolio. This might even be the case for projects without objectives of exporting to the EU, but is rather done to be able to set up strict quality objectives for their projects.

Conclusions: China embraces QbD

Our recent experience suggests that leading Chinese manufacturers not only have adopted the Quality by Design approach, but that they also fully appreciate the regulatory implications as well as the business drivers in implementing enhanced process understanding.

In applying QbD, along with risk- and science-based approaches, the Chinese are in some regards better equipped to manage the changes of the organisations that theseentail, due to the lack of quality history. Since there is a lack of understanding regarding the extent to which the new CFDA GMP will be enforced, and the similarities on paper between EU and the new Chinese GMPs, many leading manufacturers aim for compliance with EU GMP in current projects.

China’s pharma industry as a whole is still behind EU and the US in terms of cGMP compliance but the gap is rapidly decreasing. In a not too distant future, Chinese manufacturers are likely to catch up and even surpass EU and US manufacturers both in terms of compliance and quality performance. However, China still has issues with management, leadership, innovation and creativity that are slowing the pace of the development down for the time being. Changing this probably presents an even bigger challenge than implementing new industry regulations and guidelines.

Authors

Erik Östberg: Project Validation Manager Pharmadule Morimatsu China.
Erik Östberg has eight years of experience from the Life Science industry and has worked for many multi-national manufacturers. He is specializes in management of complex validation projects. Erik lives in Shanghai since 2011. He holds a Master’s degree in Biochemical Engineering from Chalmers University of Technology in Gothenburg, Sweden.

Daniel Nilsson: Director GMP & Validation Services Pharmadule Morimatsu China.
Daniel Nilsson has more than 15 years experience from the (bio) pharmaceutical industry spanning all different areas of validation and QA work, and management consulting, for multi-national and Chinese manufacturers. He lives in China since 2012. Daniel holds a Master’s degree in Chemical Engineering from the Royal Institute of Technology in Stockholm.

Magnus Jahnsson: Director Regulatory Affairs Pharmadule Morimatsu AB Sweden.
Magnus Jahnsson has more than twenty years’ experience from the pharmaceutical field, both from the industry and from regulatory authorities. He has worked extensively in the fields of R&D, manufacturing, QA and regulatory affairs and has held positions with AstraZeneca, European Medicines Agency and Pharmadule.