13 Prerequisites for Successful Validation

In this article let’s understand the Prerequisites for Successful Validation and Improving Validation Processes in Pharmaceutical Firms.

Validation was implied in the 1960s, almost four decades ago. What has changed over the last 30 to 40 years? Has the overall understanding of the term improved? Have all responsible firms truly adopted validation? Are they doing everything within their power to make validations a success? Unfortunately, not. While validation is a very necessary element of any firm that falls under the scrutiny of the governing regulatory agencies – both United States and foreign – it has not received the recognition it deserves.

So often, departments charged with conducting validations are forced into an exiled status, as opposed to being adopted.

A firm derives little benefit if a thorough understanding of validation remains within the validation department, and there is absolutely no concept of the term within the department responsible for approving the validation budget.

• How can validation professionals bring about a change?
• How can they ensure that proper events occur to achieve successful validation?
• Why has validation been so misunderstood for the last four decades?
• How can validation resources go about planning and executing validations?
• How can a firm be assured that its resources have what it takes to successfully complete a validation?

13 Tools or elements required for conducting effective validations:

There are thirteen tools or elements required for conducting effective validations. Each is presented and discussed in the following sections of this article.

1. Understanding

Perhaps the single most important element required is a good understanding of what validation is. This understanding actually goes beyond the basic definitions of validation, beyond the concept of “requiring a minimum of three runs.” This understanding must be anchored by sufficient years of practical experience and knowledge. It will permit sound and logical decisions, even under the most intense situations.

Given the fact that regulated drug manufacturers must perform validations, it is very important that this understanding be shared throughout the organization. A firm derives little benefit if a thorough understanding of validation remains within the validation department, and there is absolutely no concept of the term within the department responsible for approving the validation budget.

So often, validation becomes alienated from the rest of the company due to a lack of thorough understanding. Why can’t the laboratory use the piece of equipment undergoing validation? Why can’t the facility be used before the laboratory has completed the analysis of the microbiological data? Why are validations so expensive? Naturally, if the entire company is fairly educated on what validation entails, less time will be required to defend validation’s actions. Good understanding has to be disseminated throughout the entire organization. Of course, it has to begin with the group charged with performing validations. In the end, it is up to the firm to realize the importance of assuring that, this understanding is shared among the key groups.

2. Communication

One of the best methods of improving environmental understanding is through communication. Communication is essential for any activity that requires more than one resource to complete. Hopefully, this point is understandable considering that conducting effective validations involves multi-departments.

Typical questions such as:

• When is validation of unit XYZ scheduled to begin?
• How many resources will be required?
• When do protocols have to be approved?
• At what sites will sampling occur?

These are best answered through communication. One of the keys to proper communication is locating the right communication vehicle. Most organizations communicate through one or more of the following methods:

• Conversations
• Memos
• Periodic meetings
• Training sessions

While adequate communication can be obtained through any of these methods, the ideal environment would have all of the above. The point is that some communication is better than no communication.

3. Experience

A firm must have resources with solid validation experience for its validation program to be successful. Can the average person be expected to perform open heart surgery without proper study/ preparation? More simply, can the average person be expected to win a bike race if they have not yet learned to ride a bike? If one has not shouldered the responsibility of performing an Installation Qualification (IQ) on a pump, will they be able to execute the Operational Qualification (OQ)? Well, this same concept holds for a person charged with planning or executing validations.

The point is that the more responsibility a person has shouldered for validation, the greater their experience will be. Likewise, their knowledge, understanding, and logic will be greater. For example, a seasoned validation resource, in the midst of completing a validation, encounters a failure that will necessitate validation to be repeated in its entirety. Working through this series of events will undoubtedly provide the resource with experience in dealing with failure and resolving problems.

Now, is it reasonable to expect an inexperienced staff to perform a solid validation? In most cases, no. However, with proper coaching and consultation, some successes can indeed be realized.

4. Cooperation and Focus

Why is there a need for cooperation in order for personnel to conduct effective validations? Let us first understand the multitude of departments that sometimes interact during the course of executing validation:

• Program/Project Management
• Accounting
• Validation
• Quality Control (QC)
• Project Engineering
• Process Engineering
• Quality Assurance (QA)
• Metrology
• Facilities
• Regulatory, etc.

It is safe to assume that these departments have an array of priorities, and typically they are not the same as validations.

Let us focus on the example of a professional basketball team. Their objective parallels that of a multidisciplinary/inter-departmental validation team—both strive for success. The assumption is that each team member is critical to the overall success of the team. Assume that both teams are in the fourth quarter or final phase of their event—the basketball team in the championship game, and the validation team executing the final event prior to initiating product commercialization. If the center on the basketball team loses his desire to play defense and/or pass to his teammates, how successful will that team be? The same concept applies to the validation team. If someone fails to approve the protocol or to sample per the protocol, the cost of validation will undoubtedly increase. Why? Simply because more time will be spent seeking approvals. Likewise, time will be spent justifying and writing the explanation for why a Sample was not actually retrieved. Cooperation is crucial and essential. Therefore, each personnel should be geared and ready to cooperate 100%.

5. Resources

In actuality, it does not count how much knowledge, experience, and understanding a firm has unless they do not place the right resources for making proper validations. What do we mean by resources? By resources, we, of course, mean personnel who will plan and execute, equipment on which validations will be performed, materials to conduct validations, laboratories to do the necessary analyses, funding to pay for the validations, and TIME in which to perform the validations. Validations can often begin but cannot be completed if any of these resources are missing.

For example: the autoclave to be validated for a new load configuration. The Equipment Owner has already defined a window time, the window equipment and all the human resources required have been made available by the owner’s department personnel, and the lab is set to receive samples laboratories. However, the validation team has received information that the laboratory does not have any spore strip materials in the inventory. Can validation be done? No, since spore strips are required to show that the cycle works. The case is the same for everything else that is needed for validation.

• Meet
• Plan
• Document the plan (protocol)
• Do the plan
• Debug and correct problems
• Summarize the work

Consider how projects are funded for in companies. Each department has to prepare an annual budget for anticipated expenses. It is very important that the expected costs are shared with upper management to ensure that ample support or funding exists. Now consider validation and the bulleted activities listed above. From a corporate standpoint, each of these elements requires time and, therefore, has an associated cost. Thus, they must be reflected in the validation budget.

So often, the wait for the receipt of analytical results causes the entire validation project to halt. Why? Because validations are based on the results obtained.

6. Budget

It is essential to understand that a successful validation must be done to completion. Usually, it should not be limited by a budget put together by people who have no appreciation for what is necessary to complete validation successfully. Further, it is essential to recognize that validations do cost money. A rule of thumb has been that equipment qualifications, which are integral parts of validations, are typically 10-20% of the cost of the capital equipment. So, where do these charges come from? Often, these fees are regarding the time to implement the following cost measures:

• Investigate/acquire information
• Conduct meetings
• Plan
• Put the plan into words (protocol)
• Execute the plan
• Troubleshoot and/or resolve problems
• Summarize the effort

Consider how projects are funded within corporations. Each department has to prepare an annual budget for anticipated expenses. It is very important that the anticipated costs are shared with upper management to ensure that ample support or funding exists. Now consider validation and the bulleted activities listed above. From a corporate standpoint, each one of these elements requires time and therefore has an associated cost. Thus, it is essential that they are reflected in the validation budget.

So often, the wait for the receipt of analytical results causes the entire validation project to come to a halt. Why? Because validations are based on the results obtained.

7. Plan

A professional sports team cannot be expected to win the championship without a plan. Most of these teams refer to their plans as plays. Without plays, a good offensive football team cannot hope for success against another good team’s defense. For example, if the quarterback does not know where his receivers will be, how often would he be able to complete a pass? If a running back did not know his team’s blocking strategy, how many yards would he average per play? Per game? Per year? Bear in mind, that conducting validations within most companies will involve a number of departments and disciplines. These disciplines need a plan in order to get good team synergy. Further, this plan must be communicated in order to be accepted and successful.

• When should the analytical laboratory receive the samples?
• How should a deviation be handled?
• How will chamber temperatures be monitored?
• When will the first event occur?
• Will manufacturing assistance be required to execute the validation protocols?

It is essential that the lead validation resource know the answer to each of the above questions, and assure that they are shared in pre-validation planning sessions.

8. Training

Training is essential for any successful validation. Even though the group charged with gathering routine Water-for-Injection (WFI) samples from the plant distillation system knows how to collect regular samples, chances are they will not inherently know how and when to gather samples in support of a new sample port. Thus, the need for training. Typically, this training initiates within the validation group. It is essential that the lead validation resource for a given validation project initiate, facilitate, coordinate, and/or communicate the need for resource training. In some companies, the expectation is that validation resources provide training as required by the validation event. A c t u a l l y, the requirement for training goes beyond the act of mere teaching. The regulating bodies require proper documentation to be assembled and maintained to serve as proof that key resources have undergone required training. Proper documentation should minimally include employee identification, a description of the training course, and the date on which training occurred.

9. Standard Operating Procedures (SOPs)

SOPs capture activities that routinely occur within an organization. Departments charged with abiding by or following these SOPs must first be trained against these SOPs. Many SOPs are typically the offspring of a successful validation. In most cases, equipment operation SOPs are drafted for use during the initial phases of qualification. These SOPs often are not finalized until after the equipment’s OQ event. A case in point would be an SOP for the set-up and operation of a new piece of equipment. Often, the vendor manuals.

or the specifications will convey how the equipment is operated. In the OQ phase, this information is usually transcribed for use in the form of a draft SOP. Once the OQ steps are completed, the result should be an SOP that is finalized, approved, trained upon, and implemented for routine use. The expectation is that these SOPs are finalized before the equipment is used to support process validation.

10. Solid Quality Control (QC)/Lab Support

During most validations, some laboratory testing will be required. In most cases, this testing is handled by the QC group. In most organizations, QC will shoulder the responsibility to develop and validate the analytical methods used. QC is also expected to provide results in a timely manner. So often, the wait for the receipt of analytical results causes the entire validation project to come to a halt. Why? Because validations are based on the results obtained.

In addition, QC input is required during protocol preparation. If the QC lab lacks organization, maturity, technical competency, appropriate methods, etc. an initiative has to be undertaken to attain laboratory support through a contract laboratory.

11. Solid QA Support

All validation resources may not be the best for adhering to compliance procedures. It is therefore up to QA to thoroughly police the protocols before, during, and after execution. This policing must be against internal SOPs and external regulations. The expectation is that QA will enforce any relevant compliance issues, and will thereby prevent an unwanted discovery by auditing bodies. If an auditor uncovers a number of compliance issues, the department that will often be held accountable is QA.

It must be understood that a good QA resource often is not a resource that most other operating departments would choose as their best buddy during working hours. However, their value to the success of the organization’s validations must not be minimized.

12. Permission to Conduct Preliminary Runs ( Trials/Engineering Runs, Demonstrations, etc.)

Could one be expected to drive from Maine to California without a map? Would a map exist without some preliminary explorations? Why does an infant crawl before walking? Why do they undergo a period where they will make only one to three steps? With time, they of course, progressively make more steps until they ultimately learn to walk. Walking then becomes natural, and for the most part, faultless. When a system undergoes validation, the desire is that its operation is then faultless. Like walking, validations require practice. Given the fact that validations are typically expensive, it should be understood that anything that would assure that the costs are minimized would be an asset.

Therefore, it is advisable that permission be attained to perform some form of preliminary runs. These runs can be used to provide operator training, to investigate values recommended by specifications or vendor equipment manuals, and/or to explore any limits proposed for validation.

These trial runs have to be factored into the validation budget. While each will bear a cost, the focus should be the cost of the overall or entire validation program. Consider the OQ effort. Assume that the requisite specifications are generated, and the protocols are then assembled and approved. During execution, it is discovered that the specifications are incorrect, and therefore, multiple deviations will be generated, each requiring time to resolve. Each resolution will minimally require QA’s approval. Each approval will require time for explaining the “fix” to QA (and/or other approving departments). Typically, the result is a budget that is severely over spent and a black eye for validation.

A benefit of a dry run is less time and money spent troubleshooting or explaining issues. This is true because the debugging is planned on the front end and the impact to the manufacturing schedule should be minimized.

13. Realistic Completion Dates

Typically, the expectation is that once the requisite time has been allotted to complete three (3) runs, the system under validation is released and ready for use. Unfortunately, this is rarely the case. For example, a cleaning validation activity will require time to complete the following activities, including:

• Training
• Conducting cleaning events
• Gather cleaning samples (swabs or rinse samples)
• Obtain the microbial challenge results
• Evaluate results
• Write conclusions
• Seek and attain post-execution approval

Therefore, it should be relatively easy to see that it requires much longer than the three, basic runs. This is where a Gantt Chart or other time management tool is assembled. Validation resources typically provide input on validation tasks. The firm must understand that this is often a lose/lose situation because if the (validation) planning resource is overly optimistic, disappointment will result when the completion date is not met. Often times, commercial campaigns are planned, based upon the projected completion date. These campaigns may involve contractual commitments. If the dates are not met, money will be forfeited.

If the resource is overly pessimistic, chances are that the environment will not be ready to react when validation is completed well before the projected date. In this case, campaigns may not be pursued in a timely manner, and therefore, the opportunity to earn money may be lost. Either one of these extremes causes some degree of disarray. Thus, it is the responsibility of the lead validation resource to accurately plan, communicate, and realistically reflect the time required to complete validation.

Conclusion

Validation has been, and continues to be, greatly misunderstood after approximately four decades. Thirteen remedies have been discussed that can help make validations more successful within any organization possessing a desire to be compliant with the regulatory agencies. While some of these tools may appear to be insignificant, all are necessary. It is therefore important that firms seeking to properly execute validations, conduct a self-assessment to determine which of these tools exist within their organization, and which of these could use some form of improvement. Once this self-assessment has been completed, the firm can then take the necessary steps to bring about an improvement in the manner in which validations are conducted. The time required to affect change within the organization will be dependent upon the amount of interest that exists within the corporation’s upper management team. This is, after all, the team that is ultimately responsible for allocating and funding validation resources.

IQ: Installation Qualification
OQ: Operational Qualification
QA: Quality Assurance
QC: Quality Control
WFI: Water-for-Injection
SOP: Standard Operating Procedure