Prerequisites for Successful Validation
Charlie Neal Diosynth-RTP (an Akzo Nobel Company)
alidation was hinted 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 embraced 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 embraced.
• How can validation professionals bring about a change? • How can they assure 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? There are thirteen tools or elements that are required for conducting effective validations.
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. d
Each are 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. Afirm 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 analysis of the microbiological data? Why are vali-
Journal of Validation Technology
Charlie Neal, Jr.
dations so expensive? Naturally, if the entire company is fairly educated on what validation entails, less time will be required defending 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 involve multi-departments. • 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 typical questions that can best be 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 either one of the above, 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 in order for their 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 Qualifi-
cation (IQ) on a pump, will they be able to execute the Operational Qualification (OQ)? Well, this same concept holds true for a person charged with planning or executing validations. The point is that the more responsibility a person has shouldered for validation, the greater his experience will be. Likewise, the greater his knowledge, understanding and logic will be. 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 validationProgram/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 validation’s. Let us focus on the example of a professional basketball team. Their objective parallels that of a multidisciplined/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
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Charlie Neal, Jr.
sample was not initially collected. Cooperation is essential and critical. Therefore, each member must be focused on the overall tasks, and willing to cooperate 100%.
5. Resources In reality, it does not matter how much knowledge, experience, and understanding a firm has, if Consider how projects are funded within corpothey don’t allocate the proper resources for conductrations. Each department has to prepare an annual ing effective validations. What do we mean by rebudget for anticipated expenses. It is very important sources? By resources, we of course mean personnel that the anticipated costs are shared with upper manwho will plan and execute, equipment on which validations will be performed on, materials, with which agement to assure that ample support-or fundingto conduct validations, laboratories that will perform exists. Now consider validation and the bulleted necessary analyses, funding to pay for the validations, and TIME in So often, the wait for the receipt which to perform validations. Valof analytical results causes the idations can often begin, but cannot be completed if any one of these reentire validation project to come sources are missing. to a halt. Why? Because As an example, consider an autoclave on which a new load configuvalidations are based upon ration requires validation. A window the results obtained. d has been created by the equipment owner (time, equipment), the owner’s department has provided all the human resources activities listed above. From a corporate standpoint, required (personnel), and the lab is ready for samples each one of these elements require time, and therefore have an associated cost. (laboratories). However, the validation team has Thus, it is essential that they are reflected in the been advised that the laboratory does not have the required spore strips (materials) in inventory. Can val- validation budget. idation be completed? No, since spore strips are required in order to assess the efficacy of the cycle. 7. Plan A professional sports team cannot be expected to The same holds true for any resource required for win the championship without a plan. Most of these validation. teams refer to their plans as plays. Without plays, a good offensive football team cannot hope for suc6. Budget It is important to understand that a successful val- cess against another good team’s defense. For examidation must be done to completion. Typically, it ple, if the quarterback does not know where his should not be limited by a budget assembled by per- receivers will be, how often would he be able to sonnel who have no appreciation for what is required complete a pass? If a running back did not know his team’s blocking strategy, how many yards would he to successfully complete validation. Further, it is important to understand that validations cost money. A average per play? Per game? Per year? Bear in mind, that conducting validations within rule of thumb has been that equipment qualifications, which are integral parts of validations, are typically most companies will involve a number of depart10-20% of the cost of the capital equipment. Where ments and disciplines. These disciplines need a plan do these charges come from? Typically, these charges in order to get good team synergy. Further, this plan must be communicated in order to be accepted and are related to the time to execute the following cost successful. initiatives:
• Investigate/acquire information • Conduct meetings • Plan • Put the plan into words (protocol) • Execute the plan • Troubleshoot and/or resolve problems • Summarize the effort
Journal of Validation Technology
Charlie Neal, Jr.
• 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. Actually, the requirement for training goes beyond the act of mere teaching. The regulating bodies require proper documentation 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 manu-
als 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 upon the results obtained. In addition, QC input is required during protocol preparation. If the QC lab lacks organization, maturity, technical competency, appropriated 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 QAresource 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
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Charlie Neal, Jr.
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. Abenefit 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. Oftentimes, commercial campaigns are planned, based upon the projected completion date. These campaigns may involve contractical 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.
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 that 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. t
Journal of Validation Technology
Charlie Neal, Jr.
About the Author
Charlie Neal, Jr. is the Equipment Validation and Requalification Manager for Diosynth-RTP (an Akzo Nobel company), located in Research Triangle Park, North Carolina. He has been involved with validation for over 22 years, and has authored articles for both the Journal of Validation Technology and the Journal of cGMP Compliance. He can be reached at 919-678-4387.
Article Acronym Listing
IQ: OQ: QA: QC: WFI: SOP: Installation Qualification Operational Qualification Quality Assurance Quality Control Water-for-Injection Standard Operating Procedure
May 2003 • Volume 9, Number 3