Quality Risk Management as a Tool for Improving Compliance and E ciency

Transcription

1 PDA Journal of GMP and Validation in Japan Vol. 9, No. 2 (2007) 技術報告 Quality Risk Management as a Tool for Improving Compliance and E ciency Prasad Kanneganti, Ph. D Quality Operations Pˆzer Asia Paciˆc Pte Ltd Singapore 製剤加工は, 医薬品産業が直面している幾つかの難しい課題に対応する, 急激で根本的な変化を被っている科学ベースのツールと品質のリスクマネジメント(QRM)は, 製造業務の効率改善に益々用いられ始めている規制当局の支援を得て, 医薬品業界製造に関する知識基盤を新たに構築し,デザインスペースを確立する知識ベースを開発することに資源を投入しつつある製品のライフサイクルの全体を通じて QRM の利用に対するすばらしいビジネスの事例がある Risk Rankin と Filtering 及び Failure Mode EŠect Analysis( 故障モード影響解析 )のような QRM ツールの利用を, 提言する品質管理ラボにおける予防保全プログラムを最適化するために QRM の利用について述べている事例研究が, 以下に提示する Pharmaceutical manufacturing is undergoing radical changes in response to challenges being faced by the industry. Science-based tools and Quality Risk Management (QRM) are increasingly being used to improve the e ciency of manufacturing operations. With the support of regulatory agencies, the industry is investing in developing the knowledge base of manufacturing and establishing the design space. There is a strong business case for the use of QRM throughout the product lifecycle. Use of QRM tools such as Risk Ranking & Filtering and Failure Mode EŠect Analysis is discussed. A case study discussing the use of QRM to optimize the preventive maintenance program in the Quality Control laboratory is presented. Keywords: Quality Risk Management, Risk Assessment, Risk Ranking & Filtering, Failure Mode EŠect Analysis The pharmaceutical industry today is facing many challenges. Over the last few decades, improvements in health care have led to decreasing mortality rates and resulted in people all over the world living longer. The needs of an ageing population have become important. The complexities of diseases requiring therapy have also changed. Traditionally, infectious diseases were the primary cause of death but today cancer, diabetes and cardiovascular diseases are of concern. The cost of drug research has gone up and at the same time R & D productivity is waning. The drug industry is adversely ašected by several late stage failures of drugs undergoing clinical trials. At the same time, patent expiry and loss of exclusivity are resulting in decreasing revenues due to generics manufacturers taking over global supply quickly. The industry is also facing challenges to intellectual property. Patent challenges in the developed world are common and driven by the rewards arising from being early to market generic versions. Counterfeiting and piracy in developing countries are also major challenges for global manufacturers. Despite ešorts at harmonization of international ˆling practices, regulatory requirements are also getting to be more complex thus resulting in higher cost of goods and product launch delays. Manufacturers are today facing increasing pressure to improve e ciencies and reduce drug costs. This is ašecting the way manufacturing 96

2 Vol. 9, No. 2 (2007) Table 1 Pharma Sales (US$ Billion) 2007 Table 2 Pharma Sales (US$ Billion) Pˆzer Glaxo SmithKline Sanoˆ Aventis AstraZeneca Merck Novartis Johnson & Johnson Roche Eli Lilly Wyeth Bristol Myers Squibb Amgen Genentech Novo Nordisk Merck Serono Baxter BioScience Biogen Idec Genzyme CSL Ltd Allergan Elan 0.5 Source: Contract Pharma July Abbott Schering Plough Bayer Schering Boehringer Ingelheim Takeda Astellas Pharma Daiichi Sankyo Eisai UCB Group 4.4 Source: Contract Pharma July 2008 is carried out with more emphasis on the use of sciencebased tools and Quality Risk Management to improve operations. According to IMS Health, worldwide Pharma sales in 2007 was about US $ 663 Billion. Compared to other industries such as microelectronics and automobiles, the pharmaceutical industry is still quite fragmented with no company having even a 10 of the global market share (Table 1 and 2). Over the past few years, several mergers and acquisitions have occurred and these are mainly driven by the need to address the challenges described earlier. Driven by the need to improve both ešectiveness and e ciency, pharmaceutical manufacturing is undergoing a revolutionary change. A few years back, Dr Janet Woodcock who is a US FDA Deputy Commissioner stated that, ``Industry must reinvent itself and its relationship with FDA to deal with a future that promises to be very dišerent from today. Archaic regulatory practices that have sti ed innovation and made the industry ine cient cannot continue. Part of the problem was that we didn't know what in uenced product quality. We treated everything same, every deviation was a threat to product quality but if your processes are under control and well understood, we can do things very dišerently''. This is a clear indication to the industry to strive for process understanding based on science and to unburden the organization based on this understanding. Another senior FDA o cial, Dr Mark McClellan who was the former FDA Commissioner once remarked, ``Pharmaceutical companies must catch up with potato chip and soap ake manufacturers by modernizing operations and applying technology ešectively''. This remark has often been quoted in the media and at various conferences. I have no experience with the Food Industry but have always wondered how potato chips are packaged. They are very fragile yet you seldom see them crushed. So, out of curiosity, I did a Google search on the internet to ˆnd out how sophisticated potato chip manufacturers were. Here is what I found. In 1998, a German company named Hypersonic Technology used modeling, calculation methods and measurement techniques used for European Space Agency (ESA) spacecraft landing to develop a potato chips bagging system for Rovema, a German packaging machine manufacturer. They used mathematical modeling to carry out simulation studies and identify the optimum parameters for the packaging of potato chips! The new paradigm shift in pharmaceutical manufacturing includes use of risk management and risk tools. What is 97

3 PDA Journal of GMP and Validation in Japan Figure 1 How Q8, Q9 and Q10 Contribute to Risk Reduction risk? It's a combination of exposure and hazard. This is also sometimes referred to as probability and severity. What is the probability of a certain event such as a product failure occurring and when it occurs, what is the severity or impact to the patient. The International Conference on Harmonization (ICH) trio consists of Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality Systems (Q10). Quality Risk Management (Q9) states the following primary principles; The evaluation of the risk to quality should be based on scientiˆc knowledge and ultimately linked to the protection of the patient The level of ešort, formality and documentation of QRM should be commensurate with the level of risk Thus, the element of risk is assessed based on scientiˆc understanding of the process and quantiˆed where possible. Its important to link the risk to the protection of the patient. Risk assessment documentation is essential, however, we must refrain from making this a purely paper exercise. The ešort put in must be in line with the level of risk. Figure 1 shows how the ICH trio contribute to risk reduction. The risk tools described in Q9 can be used to reduce product and process risk during pharmaceutical development as described in Q8. Similarly, the risk toolkit canbeusedtoreducetherisktothequalitysystemas described in Q10. This ultimately beneˆts the Organization as a whole. The traditional approach to risk management is intuitive. When we have an event such as a complaint from a patient that the drug product is not ešective, we investigate by asking a lot of questions. Was the incorrect material dispensed or was the amount of active dispensed inadequate? Are other batches ašected? This is a reactive approach and does not always result in ˆnding the root cause. The Corrective and Preventive Actions (CAPA) taken are not always sustainable. QRM on the other hand is a proactive approach that requires such thinking in advance of running a process and making a product. There is a strong business case for QRM and some of the beneˆts are listed below: Prioritising/ focusing resources Eliminates non-value adding activities Unburdens the organization by reducing workload Essential for lean/ agile manufacturing Focusonmanagingriskratherthanavoidingrisk Aligned with continuous improvement initiatives Fosters Quality by Design (QbD) and regulatory exibility Greater assurance of patient safety through informed decisions Risk reduction through mitigation strategies 98

4 Vol. 9, No. 2 (2007) Figure 2 Process Capability Level in Manufacturing QRM has found widespread use recently and we are still ˆnding opportunities for using it in routine manufacturing operations. I have found its application useful in the following situations: Qualiˆcation link to Commissioning and Qualiˆcation (C &Q) Quality deviations Extent of Validation Change Management PM programs and Calibration Audit frequencies Supplier Management Elimination/ reduction of IPC testing Reduced QC testing Delegation of batch record reviews from Quality to Production Analytical method transfers Hold times Cleaning, Intermediates, etc Mode of Shipment AirorSea Utilities/ Environment monitoring In terms of process capability, pharmaceutical manufacturing today is generally at about 3 Sigma level (Figure 2). This is far behind the microelectronics industry which has attained levels between 5 Sigma to 6 Sigma. We are seeing a trend towards more process understanding thus moving from descriptive knowledge to correlative knowledge whereby we establish how the process output is related to the inputs. Beyond correlative knowledge is causal knowledge whereby we understand the cause and ešect and ultimately the mechanism of action. Our approach in the past was to carry out process validation using 3 batches. This limited the process knowledge available and each time a change was made to the process, further validation had to be carried out and reˆling with regulatory authorities. The new paradigm is to understand the design space as shown in Figure 3. By understanding the in uence of various factors ašecting the process, a set of knowledge is created and its now possible to carry out a proper risk analysis of the impact of process changes. The product lifecycle starts from development through manufacturing and ˆnally discontinuation. During development phase, QRM is used to identify what to monitor and measure (Figure 4). Co-development is the interface between development and manufacturing and during this phase, its established how to measure e.g. lab testing or process analytical technology (PAT). Figure 5 shows the 99

5 PDA Journal of GMP and Validation in Japan Figure 3 Design Space Figure 4 Product/Process Monitoring Approach risk assessment and prioritization in development phase. Of the many quality attributes, material attributes and process parameters, its required to identify what is critical. Such risk assessment and prioritization is supported by laboratory evaluation using Design of Experiments (DOE). The outcome of this activity is the establishment of Critical Quality Attributes (CQA), Critical Material Attributes (CMA) and Critical Process Parameters (CPP). Thisinformationcanbeusedtoestablishacontrol strategy and submit a design space regulatory ˆling. ICH Q9 has a toolkit for risk management. The two most widely used risk tools are Risk Ranking and Filtering 100

6 Vol. 9, No. 2 (2007) Figure 5 Risk Assessment and Prioritization in Development Figure 6 Risk Ranking and Filtering (RRF) and Failure Mode EŠect Analysis (FMEA). RRF as shown in Figure 6 is a simple analysis of multiple diverse factors. The user deˆnes the weighing for factors and the risk scores. Once a risk is identiˆed, the likelihood/ probability and severity are estimated and scored and the risks are ranked and ˆltered using set criteria (Figure 7). Figure 8 shows the template for a FMEA analysis. The sequence of an FMEA analysis is as below: Identify potential failure modes, ways in which the product or process might fail Identify potential ešect of each failure (consequence of that failure) and rate its severity Identify causes of the ešects and rate their likelihood of occurrence (probability) Rate the ability to detect each failure mode (detection) Multiply the three numbers together to determine the 101

7 PDA Journal of GMP and Validation in Japan Figure 7 Risk Ranking and Filtering Figure 8 FMEA Template risk of each failure mode (RPN=Risk Priority Number) Identify ways to reduce or eliminate risk associated with high RPNs Risk assessment tools were used in our Quality Control 102

8 Vol. 9, No. 2 (2007) Figure 9 Lab Preventive Maintenance Cause & EŠect Diagram Figure 10 Causal Tree Diagram laboratory recently to reduce the cost of preventive maintenance for laboratory equipment. Figure 9 shows the Cause & EŠect diagram for high cost of preventive maintenance for laboratory equipment. A causal tree can also be used to identify the reasons behind the high cost of maintenance (Figure 10). A value added/non-value added analysis as shown in Figure 11 was used to identify wasteful activities carried out during preventive maintenance of 103

9 PDA Journal of GMP and Validation in Japan Figure 11 FTIR Value Added/Non-Value Added Analysis a FTIR equipment. Risk assessment can be used to establish the frequency of maintenance and calibration. In our case, we decided to reduce the preventive maintenance frequency for the FTIR from half-yearly to yearly. The risk of reducing this frequency was further evaluated using a FMEA. This is an example of a practical use of risk tools in routine daily operations in manufacturing. It is however important to understand that QRM is not just risk assessment. The beneˆts of QRM are best realized when its proactively used to prevent failures. A holistic management approach that needs all functions to be involved is required. Being an enabler of continuous improvement, QRM ensures that resources are ešectively utilized. For QRM to successful, a strong leadership and clear guidance is required. We have found standardized company training and use of QRM subject matter experts useful. Pilot projects and sharing of examples across the organization will embed a QRM culture and spread its use widely. 104