The Third Planning Focus of VMPs: Validation Lifecycle Management

In addition to planning the systems inventory and the validation schedule, the VMP is a plan for validation lifecycle management. While the VMP assists with planning the design and execution phases of validation, post-validation activities are also included. A plan for managing the monitoring and control of validated systems and processes is just as essential as a plan for the design and execution phases.

Post-validation monitoring is frequently overlooked, but is an essential component of a VMP. Validation is never “done”. Validation is a quality system that is ongoing and requires maintenance, even after initial validation is complete. Therefore, the VMP must describe a plan for post-validation monitoring.

Continual monitoring of validated processes is required by regulatory agencies. FDA 820.75(b) for devices states that procedures for monitoring and controlling process parameters in validated processes must be established and maintained (1). Similar expectations are held of pharmaceutical and biotechnology manufacturers. Post-validation monitoring helps to confirm that the specified requirements of the process continue to be met. This, in turn, ensures that products continue to be safe and effective for patients.

Data gathered during validation is used for monitoring and controlling the validated state. The important output variables of the process were determined during process validation. Also, the critical quality attributes (CQA) and critical process parameters (CPP) should be known and documented. During post-validation, the output variables are monitored and the input variables are controlled.

There are several tools that can be used for post-validation monitoring. Some of these tools include:

• Statistical process control charts (SPC) used monitor and detect any process changes
• Control charts, which can be part of a capability study to demonstrate stability in the process over time
• Capability indexes that determine if the process is adequately centered with small variations
• CAPA, change control, or deviation and investigation reviews
• Trend analysis
• Alarm logs
• Revalidation
  

All of these tools can be used to monitor the process on a per-batch or per-year basis. Monitoring a process on a per-batch basis provides the lowest risk to the organization. Data is provided in real-time, which in turn, assures the highest level of quality assurance and the highest return on investment to the organization. Performing annual reviews of the data allows the big picture to be examined for trends or other indicators of process issues. Both methods can be employed when planning post-validation monitoring. Post-validation monitoring also provides benefits for other aspects of a process. These aspects include:

• Improving the quality and performance of a process, which can help a company save money
• Assisting with annual reports that may be required for some systems (e.g., Water-For-Injection system)

Post-validation monitoring can be used to not only monitor the process for continued high performance, but it can also be used to monitor business-related aspects of a process. Ultimately, post-validation monitoring can provide a real return on investment to the company beyond improved compliance.

Validation lifecycle management is an important part of any VMP. Post-validation monitoring is commonly overlooked, but is required by regulatory agencies. An adequate plan for post-validation monitoring must be outlined in the VMP. Managing the validation lifecycle via the VMP will assist with developing a process that continues to produce quality product that is safe and effective for the patient.

Any comments or questions regarding this blog are more than welcome. Thanks!

Best regards,

Megan K Gladfelter

The Second Planning Focus of VMPs: The Validation Schedule

Hello again and welcome back to my blog on validation at Kymanox! As my first post explained, Validation Master Plans are the primary tool for planning validation in the industry that Kymanox services, and there are three main planning focuses of VMPs. My last two posts discussed the systems inventory and determining the appropriate level of validation for each system. This post will focus on the second planning focus of VMPs, which is planning the validation schedule.

The VMP outlines a plan which includes the validation schedule. The validation schedule is one of the most important components of a properly written VMP. The schedule contains the activities that are going to be performed during the official validation, as well as the pre-validation activities and non-validation activities that need to be performed. There are many specific techniques that should be used when developing the schedule in a VMP. The following techniques will help to ensure that validation runs smoothly and the overall schedule can be maintained:

• Where possible, use task dependencies instead of hard dates. Equipment and laboratory methods used in a process must be validated before the process validation is performed. Cleaning validation should occur after process validation. Using dependencies as the basis for the schedule is crucial. Scheduling specific activities to be completed by specific dates (i.e. 01MAR09) will usually result in a VMP that is behind schedule by the time it is first approved. The validation schedule is a commitment, and using dependencies instead of hard dates will assist with preserving the overall schedule.
• Schedule specific time for non-validation and pre-validation activities. Validation protocols take a significant amount of time to draft, revise, and approve. Also, engineering runs, calibrations, and commissioning should be performed before beginning any official validation activities. Validation is the confirmation of a system’s operation. Therefore, validation should not be the first time the system is operated and tested. Neglecting these activities can result in unnecessary deviations during validation that could have been easily avoided.
• Include time and resources for contingencies. At least one non-conformance, deviation or variation will likely occur during validation. Resolving a non-conformance takes time and effort, which needs to be included in the validation schedule. Also, equipment may break down or the availability of raw materials could be delayed. All of these unforeseen events will require additional time. This contingency time should be built into the validation schedule from the start and clearly specified as contingency time.
• Include any up-coming company holidays, planned shutdowns, and preventative maintenance (PM) activities in the overall schedule. Quite often, projects consist of multi-company efforts and multicultural team members. Being aware of all relevant holidays will help to prevent unforeseen delays due to lack of available resources for the project. Also, planning for shutdowns and PM activities will ensure the overall schedule can be achieved.
• Schedule time for any required training that personnel executing the validation may need. Having trained validation technicians will help to ensure that all validation activities are valid. Training takes time and resources, so include it in the schedule. Also, including training in the VMP schedule will assist with demonstrating to inspectors the organization’s attitude toward the quality of validation.
• Ensure that the equipment and systems to be validated will be available for validation. If any in-use production equipment is required for validation, be sure to inform production of the validation schedule. Additional time should be included in the schedule to allow for delays in procuring the equipment from production. It may difficult to take production equipment out of service, even if production is aware of the requirements ahead of time. By keeping production “in the loop” regarding the equipment needs, the validation schedule can be maintained by preventing delays in procuring equipment.
• Maximize data collection during validation activities. One production run can sometimes be used to collect data for the equipment PQ, process validation, and cleaning validation. Collecting data for several different validation activities at the same time will minimize the required overall validation time. It can also create extra time for unforeseen delays that may delay the schedule.

The validation schedule is the primary planning tool in the VMP. The schedule is also a commitment, and changes to the schedule may raise red flags for inspectors. Incorporating these specific techniques into the validation schedule will assist with ensuring the validity of all validation activities, demonstrating to inspectors the organization’s commitment to the validation quality system, and maintaining the overall validation schedule.

My next posts will discuss the final planning focus of the VMP, which is planning validation lifecycle management and post-validation monitoring. Please feel free to contact me with any questions or comments you have regarding this blog. Thanks!

Best regards,

Megan K Gladfelter

What Level of Validation Does Each of My Systems Require?

At Kymanox, we have managed a great deal of validation projects, from manufacturing equipment to computer systems and software. As with any validation, one of the decisions that needs to be made is determining the appropriate level of validation for each system in the systems inventory. As discussed in my last post, there are a number of different levels of validation that can be performed on a given system, and the VMP must specify the level of validation that each system will receive. However, a common question that we encounter when managing validation projects is "How do we determine the appropriate level of validation since each system serves a different purpose?"

The appropriate level of validation for each system depends on the potential risk the system has on the product with regard to quality, safety, and efficacy. ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (1), and Annex 15 to the EU Guide to Good Manufacturing Practice (2) provide some general definitions and guidance for each type of qualification. Systems that indirectly and minimally impact the overall quality of the product would possible only require an IQ or a simplified combined IQ/OQ. Examples of these systems include:

• Utility systems (e.g., glycol chiller)
• Secondary packaging equipment (e.g., tape dispensers for final shipping boxes)

Any issue with these types of systems will have no direct impact to product, and ultimately the patient. Therefore, minimum validation is performed to qualify the system for use.

If a system could directly impact the quality of the product, the system will require more validation. However, if the system is not directly involved in a process method, only an IQ and OQ may be necessary to ensure the system is capable of performing as intended within normal operating parameters. In some instances, an IQ, OQ and equipment-based PQ may be required. Some examples of systems that might fall into this group are:

• A product holding tank with no critical operating parameters such as heating or cooling liquid to a specific temperature
• Mixers for simple tanks and solutions
• A remote printer for printing manufacturing trends

A fault in these systems may not directly impact the final product. However, these systems must be functioning properly for the overall process to function. As a result, more validation is performed to qualify the systems.

If the system has a direct impact to the safety, quality, or efficacy of the product, the system will require a much more extensive validation. This also applies to systems directly involved in a portion of a process method. There are many validation level combinations that can be performed on each system, including those systems with direct impact to the product. Examples of such systems may include:

• Environmental chambers
• Chromatography systems
• Bioreactors
• Packaging and labeling equipment

An error in one of these systems could directly affect the product and patient - and therefore require more extensive validation.

When making the final decisions about the level of required validation, the Regulatory and Quality Assurance groups must be consulted. This will ensure that the overall validation approach is minimally sufficient, defendable, and in line with current industry practices and FDA expectations. The examples provided herein are simplified hypothetical scenarios; your scenario may be different and require a different approach.

Medical device systems have an additional decision that must be made when determining the required level of validation. Validations for medical devices do not always need to be performed. Process verification – usually by 100% visual inspection – can be performed in place of validation for some types of processes. The GHTF guidance on process validation (3) provides detailed information on validation versus verification decisions.

The decision to verify rather than validate is centered on the process output. If the process output is fully verifiable by inspection, verification can be performed in place of validation. However, it must also be sufficient and cost effective to verify rather than validate. If the process output cannot be fully verified by inspection or it is not sufficient and cost effective to verify, then process validation will most likely be performed. The systems inventory should contain a column for verification for any medical device systems to ensure the validation has been effectively planned.

It is also essential that there is a general understanding of the overall process in order to avoid over-qualifying the systems. It is always “better to be safe than sorry”. However, over-qualification due to a lack of knowledge adds a great deal of time and cost to validation. When there is a detailed understanding of the process, reduced validation can be justified. This risk-based approach is consistent with guidelines outlined in ICH Q9, Quality Risk Management (4), and GHTF guidance on implementing risk management principles (5). Specifically, a lot of software packages are over-validated as compared to their actual use and impact to the product and patient; in many cases, a black-box approach to testing software is sufficient and can save considerable time and money which can be spent on systems needing additional validation attention.

A sampling strategy with statistical justification must also be described in the VMP for the systems in the systems inventory. The pre-determined sampling plan is combined with the pre-determined acceptance criteria in the specific validation protocols. Gone are the days of N=3 as acceptable default sample sizes. The new expectation is that a statistically justified sampling strategy is implemented for all validation activities and documented a priority.

There are several methods for determining appropriate sampling strategies with statistical justification. The methods include:

• Performing pre-validation activities (engineering runs)
• Utilizing commissioning data
• Applying previous knowledge or experience with similar equipment, processes, etc.
• Using estimates of variability (standard deviation) based on data from pre-validation activities and previous knowledge of the systems
• Employing documented risk assessments for reduced sampling

Performing pre-validation activities is the most useful method for determining an appropriate sample strategy, and therefore sample sizes. Pre-validation helps identify behavior and variability in the systems. Also, performing pre-validation activities will save time, money, and various quality-related issues during validation execution. Whatever method is utilized to determine an appropriate sample strategy for validation, the determination process must be documented in the VMP.

My next post will move on to discuss the second planning focus of VMPs, which is planning the validation schedule. Please feel free to contact me with any questions or comments you have regarding this blog. Thanks!

Best regards,

Megan K Gladfelter

References:

1. ICH, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 10 November 2000.
2. Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice, Qualification and Validation July 2001.
3. Quality Management Systems - Process Validation Guidance, Document Number GHTF/SG3/N99-10:2004 (Edition 2) January 2004.
4. ICH, Quality Risk Management Q9, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 09 November 2005.
5. Implementation of Risk Management Principles and Activities within a Quality Management System, Document Number GHTF/SG3/N15R8 20 May 2005.
   

The First Planning Focus of VMPs: The Systems Inventory

Hello again! Welcome back to my blog, which focuses on the validation in the Pharmaceutical, Biotech, and Medical Device communities. As I mentioned at the end of my last post, validation master plans have three main planning focuses, one of which is the systems inventory.

The VMP contains a plan for the systems inventory. The systems inventory lists everything requiring validation. It also captures the required level of validation for each system. Refer to Figure 3 for an example systems inventory.

Figure 3. Example systems inventory in a VMP

There are many systems that can be listed in a systems inventory depending on the scope of validation. Some examples of systems included in the systems inventory are:

• Equipment (e.g., freezers and incubators)
• Manufacturing processes (e.g., manufacture of arterial stents)
• Cleaning processes (e.g., CIP processes)
• Analytical methods (e.g., UV assays)
• Computer systems (e.g., electronic batch records and document repositories)
• Utilities (e.g., WFI and nitrogen gas)
• Facilities (e.g., ISO Class 7 cleanroom)
• Materials (e.g., syringes for injecting drug product)
• Critical Operator Processes (e.g., operators performing the aseptic gowning technique for entry into an aseptic filling suite)

The systems inventory is a living document. The systems inventory should be attached as a reference in the VMP rather than reside within the VMP. The systems inventory must be updated as often as needed based on validation scheduling and scope changes. It must be an accurate representation of the validated systems. The VMP will be viewed by inspectors who will expect the attached systems inventory to be a comprehensive list of the validated systems.

The systems inventory is a very useful component of a VMP. It provides a clear picture of the systems to be validated and outlines the level of validation required for each system. A general understanding of the process is required when creating the systems inventory to ensure that over-qualification or under-qualification of the systems does not occur. Appropriate qualification levels for each system, along with an adequate sampling strategy, will save time and resource requirements during validation.

As previously mentioned, the systems inventory identifies the required level of validation for each system. There are several levels of validation that can be performed. The most common levels of validation are:

• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)
• Method Validation (MV)
• Process (Product) Validation (PV)
• Cleaning Validation (CV)
• Computer System Validation (CSV)

The terms for the various validation levels may vary even though the concepts are generally the same. For example, a recent draft of FDA guidance on process validation lists “process qualification” as a stage of process validation in the product lifecycle (1). Terminology in the industry is constantly evolving. As a result, different companies may use different terminology. Be sure to use the terminology specific to the company to avoid confusion and ensure there are no validation gaps due to misuse or misunderstanding of terminologies.

Another item to note with regard to the validation levels involves Process (Product) Validation (PV) and Cleaning Validation (CV). Although PV and CV are listed separately, CV is a specific type or subset of PV. When creating the systems inventory and determining the required level of validation, it is perfectly acceptable to include CV under PV or keep CV separate.

There are several regulatory guidance documents that can be used when performing either Method Validations or Computer System Validations. Most current Method Validations are performed by following ICH Q2(R1), Validation of Analytical Procedures: Text and Methodology (2), USP <1225> (3), or the Global Harmonization Task Force (GHTF) (www.ghtf.org) guidance (4). For Microbiological Assays, the following USP chapters can be used for guidance:

• USP <85> for Endotoxin Inhibition/Enhancement (5)
• USP <71> for Sterility - Bacteriostasis/Fungistasis (6)
• USP <61> (7) and USP <1227> (8) for Bioburden - Bacteriostasis/Fungistasis

Nowadays, Computer System Validation is typically performed by following GAMP® 5 guidance (9) from the International Society for Pharmaceutical Engineering (ISPE) in conjunction with the minimum validation language addressed in the drug and device GMPs. Both Method Validation and Computer System Validation may require more regulatory guidance due to the increased complexity of the tested systems, and the above references are a good place to start.

My next post will continue the discussion of the systems inventory and focus on determining the appropriate level of validation for each system. Please feel free to contact me with any questions or comments you have regarding this blog. Thanks!

Best regards,

Megan K Gladfelter

References:

1. FDA, Process Validation: General Principles and Practices, Guidance for Industry (Draft), United States Food and Drug Administration, November 2008.
2. ICH, Validation of Analytical Procedures: Text and Methodology Q2(R1), International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use November 2005.
3. United States Pharmacopeia, USP <1225>
4. Quality Management Systems - Process Validation Guidance, Document Number GHTF/SG3/N99-10:2004 (Edition 2) January 2004.
5. United States Pharmacopeia, USP <85>
6. United States Pharmacopeia, USP <71>
7. United States Pharmacopeia, USP <61>
8. United States Pharmacopeia, USP <1227>
9. ISPE GAMP® 5: A Risk-Based Approach to Compliant GxP Computerized Systems. International Society for Pharmaceutical Engineering 28 February 2008.

Welcome Message & Introduction to Validation Master Plans

Hello and welcome to my first blog! I must admit that I am fairly new to the whole "blogging" scene but I do hope that this blog, and the subsequent posts that will follow, can be of great use to those individuals and organizations who are my target audience.

I work for a company called Kymanox (KI’-MAH-NOKS’), which means Ideal Knowledge Transfer. Kymanox is dedicated to assisting companies and individuals with knowledge transfer on a project-by-project basis. Our specific area of focus is the Biotechnology, Pharmaceutical, and Medical Device communities.

Working for a company whose focus is Ideal Knowledge Transfer ultimately means that my goal for this blog is to transfer my specific knowledge on pertinent topics in the industry to you, my audience. What specific knowledge do I have, you might ask? Well, over the past year and a half, I have spent a great deal of my time working on numerous validation projects, ranging from equipment validations to computer system and software validations. I have also authored an article for the Journal of Validation Technology on Planning Aspects of Validation Master Plans. Finally, Kymanox offers downloadable templates and training packages specifically on validation at our KymaSTORE, many of which I have contributed to. As you can see, Kymanox, and I, have a great deal of knowledge on the topic of validation.

Introduction to Validation Master Plans

Because Kymanox's focus is the Biotechnology, Pharmaceutical, and Medical Devices communities, validation is a critical component to companies and organizations within those communities. Anyone who is experienced in validation and compliance often mentions that the most important activities associated with validation are strategy and planning. In reviewing FDA observations related to validation, it is noted that there have been multiple observations and citations in which organizations did not adequately address strategy and planning in their validation programs. This is evidenced by FDA's comments on the organizations' Validation Master Plans (VMP).

Interestingly enough, a search of FDA guidance documents finds that only the Center for Devices and Radiological Health (CDRH) guidances on devices and combination products reference the need for VMPs to exist. However, almost no additional detail on VMPs is provided in those guidances. The European Union Guide to GMPs does provide a little more direction on VMPs in Annex 15, Validation and Qualification, by stating the need for validation programs to be documented in a VMP or equivalent document and what topics the VMP should address.

While the VMP is the primary tool for planning validation, it is not a stand-alone document. There is typically a hierarchical structure to VMPs. Figure 1 below shows possible hierarchy options for VMPs.

Figure 1. Possible Hierarchy of VMPs

This hierarchy of VMPs implies that each VMP must have clear scope sections to identify the relationships with other VMPs and explicitly state what is included and excluded. In many instances, VMPs are nested documents, which is illustrated below in Figure 2.

Figure 2. Example Nested Hierarchy of VMPs

The highest level of VMP (e.g., Global VMP) accomplishes the following objectives:

• Defines terms
• References regulatory requirements
• Graphically displays and discusses the validation process steps
• Identifies the requirements to validate various systems
• Identifies the requirements for planning, risk management, qualification, and statistical analysis.

The next level of VMPs (e.g., Site VMPs) describes the procedures to meet the requirements specified in the overall governing VMP. The site VMP can serve as commitment document, policy document, and planning document. The site VMP is specific to each site and includes the following items:

• Description of the site, process, and products
• Systems inventory with the required level of validation for each system
• Timeline, or schedule, for achieving the validation requirements
• Plan for post-validation monitoring and validation lifecycle management

A process-specific VMP includes much greater detail on specific processes than either a global or site VMP. The process-specific VMP helps to define a complete validation system in conjunction with the global and site VMPs.

As you can see, VMPs are much more complex than just a single document. And yet, with little instruction on what they should contain, FDA expects that organizations have VMPs to support the planning and strategy of their validation programs.

Now that I have covered the basics on validation master plans, I feel that I can better explain, in detail, how validation master plans are used to plan validation. My subsequent posts to this blog will cover the three main planning focuses of VMPs in validation, which are:

• The systems inventory
• The validation schedule
• The validation lifecycle management

Please feel free to contact me if you have any feedback or suggestions for this blog. As I stated before, the goal of this blog is transfer my knowledge of validation and validation master plans to you, my audience, so you may find this as a useful resource for daily work applications in your industry.

Best regards,

Megan K Gladfelter