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Process Validation: Thoughts on a New Guidance for an Old Issue

In January 2011 we saw another significant document issued by the FDA to provide updated thinking on Process Validation. The document entitled Process Validation: General Principles & Practices is a further extension of the progressive thinking that’s embodied in the ICH documents, Q8,Q9 & Q10 dealing with Pharmaceutical Development, Quality Risk Management & Pharmaceutical Quality Systems respectively.
In building on those ideas the new guidance is requesting an updated three point process which covers a Process Design phase, followed by Process Qualification & Process Verification phases.
In real terms what this, means is an emphasis on upfront thought about the whole process you’re developing to make your favorite products, focusing on building a robust platform of data upon which to design a sustainable qualification program.
Phase two is an emphasis on a “World Class Approach” to testing and control of all the critical process attributes that allow one to demonstrate control and complete process capability metrics for the manufacturing process one is launching.
This is a comprehensive all –inclusive approach that covers;
• Tests and studies to perform
• Criteria to assess the outcomes
• The timing of the various activities
• The responsibilities of the various parties and departments involved
• The documents needed to support & run the various activities.

Phase three is the continuous verification section/phase where one tests the reliability and sustainability of the qualified process on a continues basis through the collection of real-time process data rather than relying on three PQ runs as the industry performed for over 30 years.
This process has been welcomed by industry because it demonstrates the real capability of an industry manufacturing process, rather than the previous mechanism which pharmaceutical consultants and others have for years been drawing attention towards, and stressing the weaknesses of.
Planning and Risk Assessment is a significant piece of Process Validation today and pharmaceutical consultants experienced in Process and Quality Management System Analysis can help product companies to develop a Lean winning strategy that will meet the demands of the regulatory climate.
Over the coming years it will be interesting to observe how this affects the quality of manufacturing performance and related regulatory compliance for Life science manufacturing processes.

Metrics and their Importance in Lean Biomanufacturing

There is no doubt that metrics are an important component of any well run pharmaceutical process. Without knowledge derived from the data that details the critical process parameters, it is like running blind into a storm without a compass or GPS with which to navigate.

Modern biopharmaceutical processes are extremely complex and require synchronization of many process parameters. Without this attention to detail, it is impossible to generate the type of operating capability that produces a consistently made product with very tight technical and quality specifications.

In developing Lean approaches to these manufacturing processes, metrics provides the information which is the life blood from which biochemical engineers can balance the needs of meeting quality specifications with running the process plant as efficiently as possible.

A key metric in any biological process is the changeover time, since this is where production time is lost. As a result this is a valuable data set that requires keen focus by the operating group so that maximum productivity can be realized from the biopharmaceutical production plant.

Today, many biopharmaceutical plants run as multi-product facilities, so maximizing this changeover time is critical to maximize the plant’s operating capacity.

That said, even in the case of single product facilities, reduction in batch to batch turn around can also have a marked effect on the ROI for the plant provided that key unit operations like inoculum preparation and work up can be appropriately synchronized to assure that the tanks are ready to be re-inoculated with the next batch once they have been cleaned and re-sterilized.

This should be a key area of focus for both fully integrated companies that have their own facilities or CMO’s that provides manufacturing services for client companies. In either case, lost production time has an impact on both business models, although for CMO’s there may be a greater pressure because their income stream is entirely tied to throughput from their plant and not through revenue generation from product sales, unlike innovator companies.

Through careful application of process analytics, often with the help of pharmaceutical consultants, winning strategies can be developed to assure a “Right First Time” mentality is instilled in the operating culture, which enables this approach to make a meaningful impact on downtime reduction and production cycle time.

Change Management; A Vital Part of the Lean Mechanism within the Life Sciences Industry.

The deployment of any successful Lean initiative will be largely dependent upon the capacity of the organization to adopt the changes that are part of the overall approach and a major driver for this will be how the workforce chooses to embrace the methodology involved. Within the Life sciences Industry, this effect is often even more pronounced due to the highly regulated nature of the business processes involved.

No matter how effective the methodology is, if it is not welcomed, embraced and incorporated with enthusiasm, then it is unlikely that a sustained return on investment will be achieved.

Due to cultural, regional, age, educational and gender differences, new ideas and information will be received, processed and incorporated at different rates, so an analysis of what you have at your site should be a key part of any approach before systems are rolled out.

This stakeholder analysis should be part of any Risk Analysis and mitigation plan that is performed prior to deployment and before any deployment plans are finalized. Often this is best performed by an outside group such as a pharmaceutical consulting company, because this allows for a more objective assessment to be developed.

One key point to address is to define for the workforce what the new “Desired State” for the company looks like. It’s very important that the management and workforce clearly understands what they are working towards and how they know when they have arrived at that point.

Goals and objectives will be part of that end point and it should be clear that success will be attained when those points are reached. At that point there should be a clear understanding of how the company should recognize that success and there should be a plan in place that provides incentives to the workforce to move towards the “Desired State.”

In summary then, true success and ROI for a Lean initiative will be attained when there is a melding of the involvement of the workforce with the clear intent of the company objectives and the mechanisms and tools to assure that the “Desired State” will be reached on budget ,on-time and delivers the promised added value to the company business.

Eliminating Pharmaceutical Manufacturing Chaos through Implementation of an Effective 5S Program

From our experience most mature pharmaceutical plants contain equipment which is unused or stored within the confines of the “active manufacturing space” where the chemical/biochemical process is operating.

In most cases this is at best clutter which prevents efficient use of the space on the manufacturing floor. In worst case scenarios it is actually a massive impediment because it often prevents material, product, or personnel flow during the operation of the process.

Work arounds are often the result and inefficiency together with an increase in work related mistakes is the eventual outcome.

Whatever the outcome you choose to define, the impact on the manufacturability is to affect at least one of the following:

decreased finished goods productivity, increased cycle times, raised error frequency, increased waste production, increased accumulation of WIP (work in progress) and a disruption in workplace organization.

All of the above contribute to an unsatisfactory situation that must be resolved before a World Class Manufacturing situation is realized.

5S philosophy addresses this problem head on as follows:

1. Sort: Only equipment and other items required to meet the manufacturing function are retained in the designated space. All other equipment is removed and either disposed of or returned from wherever it originated.
2. Straighten :Once the above is complete, the essential equipment and instruments are appropriately labeled and put in a logical designated place within the space so that they can be easily found and used when required.
3. Scrub: The place should be spotlessly cleaned and maintained to present the best and most uplifting workplace for the personnel to work in, as this is known to affect labor related productivity and accuracy. It is also a primary visual mechanism in the detection of an equipment failure, for example if there is a fluid leak. Leaking onto the floor of a clean work space aids in easy and early detection compared to a dirty and cluttered workspace.
4. Systematic: Now the space is clean and orderly, a process to maintain this condition should be established to assure consistent and sustained performance.
5. Standardize: This process is involved in the crystallization of new working habits associated with the clean and organized work areas. This requires good procedures, training and commitment from the workforce including management and shop floor personnel if lasting sustainable performance is to be realized. Success will require constant attention so that new working practices become habits which are automatic actions of human behavior.

Achieving successful 5S implementation like all of Lean implementation will require significant commitments from senior management and the workforce to overcome the inevitable resistance that is naturally associated with significant change.

Overcoming this resistance through cultural change will be the real challenge in implementing this Lean tool, but organizations should persevere to reap the benefits that long-term implementation will bring.

Visual Factory Methodology to improve Lean Manufacturing in Life Science Product Companies

When employing a Lean approach to pharmaceutical (Life Science) manufacturing, the implementation of a Visual Factory Methodology as part of the approach can have a very significant impact.

The goal of Visual Factory implementation is to permit the very efficient transfer of information that can have a material effect on the performance of the manufacturing plant. Two parts are critical in implementing this:

 - Deciding what the necessary information is that needs to be conveyed.

 - Providing the most appropriate mechanism to assure that this conveyance occurs effectively.

To accomplish this objective then, it is very important that the factory operating team has a clear understanding of the “current state” situation at the plant as well as what level of performance they want to transition too. By knowing this information, the team can focus on the conveyance of that information which will bring about that change.

Frequently this will be through the implementation of new practices driven from data gathered through metrics collection and analysis processes.

Such new practices often include the implementation of new signs, charts and andons. Andons are mechanisms which employ light to indicate/transmit information such as with the use of Real-Time controllers for example.

Pharmaceutical Consultants & Life Science Consultants skilled in these ideas and their use in Lean Manufacturing strategies understand that the use of these visual techniques in manufacturing plants allow more information to be conveyed and this reduces errors significantly.

With such gains to be made using Visual Factory Methodology, we believe it should be part of every pharmaceutical & Life Science Product company’s manufacturing strategy.

Lean Enterprising; A term coming of age in the Implementation of Lean in the Life Science Industry

As Lean manufacturing makes an increasingly bigger impact on pharmaceutical manufacturing and Life Science Product Companies in a wider sense, the terminology of Lean Enterprising is becoming more commonplace.
Traditionally the focus has been to initiate Lean manufacturing and specifically the elements surrounding the shop floor production systems that impact this. However, today the emphasis is more on a general holistic implementation which covers the whole business “enterprise” network.
As a result more integrated approaches now involve the inclusion if IT/IS systems and networks, production control systems, supply chain and supplier networks, compliance & regulatory systems and the use of the organization’s human resources..

Proper integration of these factors, where there is a focus on proper human resource development & their application to waste minimization, and an emphasis on customer driven production, is at the heart of the new 21st Century paradigm for the industry. It’s also the mantra of Lean pharmaceutical (Life Science) consultants as they prepare to influence the industry to perform in the modern market place.
With such an uptake in this philosophy, there should be an noticeable improvement in the industry’s ability to meet the demands of a global market place where price is driving many companies to transfer their operating units to China and elsewhere.

The next 5 years should be very interesting!

Poka-Yoke as a Mechanism to Assure Reliable Production of Pharmaceuticals and Other Life Science Products.

Reliable performance is a must in any industry but no more so than connected with the production of Life Science Products such as pharmaceuticals and medical devices.
Poka-Yoke, the Japanese term used in Lean operations refers to the process of mistake proofing or providing a fail safe mechanism that will assure reliable operation. Eliminating defects or preventing operational mistakes can have a major effect on process capability, product specifications and operational efficiency, just to mention a few areas of advantage, so it must be given a much higher priority in our industry than currently is often the case. In our experience we could quote case histories for the following examples which are by no means uncommon or unrepresentative of the types of issues that require attention:
1. An absence of a mechanism between harvest and drain valving arrangement which have seen operators flushing millions of dollars of product down the drain. Use of an interlocking valve system, valves of different sizes or even different connectors might solve this issue.
2. Failure systems that did not fail closed results in loss of product or contamination of product.
3. Mix ups in products due to transfer of product dust as a result of improper air flows between adjacent pressurized rooms.
4. Double mechanical agitator seals installed incorrectly in bioreactors causing lost batches due to contamination problems.
5. Steam traps on sterilized systems connected incorrectly or not opening at all leading to contamination issues.
6. Flow values installed backwards.
7. In QC laboratories, analysis errors due to the analysis being started prior to the system meeting stable system suitability requirements.
8. Inappropriate use of dispensers in media preparation for bioreactors resulting in X10 components added to the media or buffer solution damaging the yield of the production batch.
Clearly these examples are all avoidable provided a comprehensive Poka-Yoke program is included as part of an overall Lean strategy. Hopefully companies will begin to appreciate the importance of such programs.

Lean Philosophy and the Life Science Industry

It’s generally accepted that standard Lean approaches have not been well implemented in the pharmaceutical industry.  We feel that this is largely  due to a lack of appreciation of the complexities of manufacturing according to cGMP which is a necessity to be in regulatory and quality compliance.

Although many of the basic principles of a Lean philosophy can be applied to the highly regulated Life Science Industry, implementation is often more complex due to the very stringent requirements for thorough and comprehensive documentation and independent quality verification.

What is required in applying Lean to the Life Sciences Industry is a clear understanding of where regulations require commitments and specific actions even though a value stream analysis may show those actions to cause a bottleneck.

Making pharmaceuticals and other Life Science products is a complex marriage of biology, chemistry, engineering and regulatory compliance. Get one of these out of balance and the process will fail for a variety of reasons.

Integration of primary synthesis unit operations with those for recovery, purification and subsequent formulation and final finishing requires many break points, testing points and detailed production records. These are the elements that help define a process and often how this process is operated defines the chemistry and pharmacological activity and utility of the product.

It is these factors that one needs bear in mind when adapting the principles of Lean to the Pharmaceutical and Life Science Industries.

Risk Management as part of your Lean Compliance Strategy to enable you to meet your Compliance Obligations.

In a regulated industry like the Life Sciences Industry which covers Pharmaceutical, Biologics, Biotechnology Drugs, Medical Devices, Medical Device/Drug Combination Products, Diagnostics and Tissue Therapies, adherence to strict regulatory& quality compliance  principles is a given. However, over killing what you are doing can be very costly and may be forcing cuts in other vital areas of the commercial operation. That’s why using Risk Assessment Techniques to develop a Lean Compliance strategy is a must today. This type of approach helps to define exactly what’s required to provide the appropriate level of coverage to assure compliance and meet the needs of ICH/FDA and other international regulations & guidance’s as well as maintaining a competitive edge to assure your company’s leadership position in the market place.

Through the application of Lean Compliance, you can meet your regulatory obligations and maintain your competitive edge!

A good example to illustrate this is the Risk Assessment of environmental  monitoring plans to determine the appropriate level of sampling required to assure environmental control while staying within the requirements to operate an effective program.

Studies indicate that savings for modern biotechnology production facilities can be in the millions of dollars per annum due to the reduction in testing materials, testing and labor required to collect and test the samples.

Determining sample plans using a simple Risk Assessment Matrix can have a drammatic effect on this process which in turn has a material effect on the ROI for the plant.

This is an example of how Risk Assessment as part of an n overall Lean Compliance Strategy can impact the competitiveness of a modern manufacturing process. Pharmaceutical constants that are knowledgeable in Lean Management and Compliance Risk Assessment are a good resource to help initiate these types of programs so you can reduce that burden immediately without jeopardizing compliance.

The Use of Process Mapping, Value Stream Mapping and Score Cards in developing a Lean Culture in Life Sciences Companies.

The Life Sciences Industry which cover pharmaceuticals, biopharmaceuticals, biologics, diagnostics, cell & tissue therapeutics, medical devices and medical device combination products, make the  treatment and use of these techniques & tools more complex than other industry sectors like automotive and microelectronics for example.

Principle among these is the regulatory environment that the industry operates within which is policed by agencies like the FDA, MHRA (in the UK) & EMRA (in the EU).

This plays a significant role in changing how certain elements are used and makes the opportunity for successful implementation more of a challenge.

That said simple techniques such as Process Mapping, Value Stream Mapping & the use of Score Cards are often employed sparingly to the detriment of the operating company. In our experience, simply by initiating the use of these tools and techniques, massive gains can be made in the streamlining of processes which result in huge savings as a result of the removal of waste.

In our experience, we have found that most companies follow a pattern of “Invented Here” philosophy which is a culture that inhibits their ability to break out and be truly innovative. This sadly results in wasteful & inefficient practices which ultimately hurts the company’s productivity and profitability.

However, positive case studies show that once initiated, programs using these simple tools can produce sustainable programs and this is possible through the participation in metrics gathering and publication of the results which identifies the direct contributions being made by the workforce to the success of the company.

Perhaps a key to successful implementation of Lean in the Life Sciences Industry is to fully engage the workforce in order to demystify the purpose.

Something to think about.