Maximize the value of your cleaning validation program through holistic project management.

In a world where information overload is all too common, it is easy to succumb to the temptation to narrow one's focus, ignoring anything that seems extraneous. This attitude is often reinforced by certain organizational structures that do not encourage personnel to look beyond their individual or departmental bailiwicks.

This compartmentalization comes at a cost, ranging from inefficiencies to outright errors and even injuries that might easily have been avoided. The good news is that by being cognizant of areas outside his or her traditional zone of awareness, the pharmaceutical project manager responsible for cleaning validation can develop a program with a positive impact that reaches beyond compliance with GMPs.

Cleaning validation is a process validation based on well-defined processes with known critical process parameters and critical control points.

All cleaning process validation projects must incorporate and satisfy governmental regulations. They also must verify that a robust manufacturing unit operation that contributes to the organization's efficiency, effectiveness and profitability has been put in place.

This article describes the critical success factors necessary to develop and manage a successful cleaning validation project and addresses the business case concerns that an effective project manager must integrate. After all, a scientifically defined cleaning process and subsequent validation can yield the best solution for maximizing production capacity, minimizing downtime and maintaining full GMP compliance.

Science and GMP: The sine qua non of cleaning validation.

Numerous tasks need to be accomplished in order to have a sound cleaning validation program and complete successful projects. Science and GMPs are key elements.

The first task is to understand and embrace the critical success factors in the creation of a cleaning validation program as embodied in a cleaning validation master plan. Those elements include both a well-defined cleaning process and a well-thought-out (and defendable) rationale for validation.

The cleaning process for a specific target entity starts with a scientific rationale and a risk-based approach to the entity. The question is, what risk does the entity pose to the product quality and the patient?

The answer will drive the critical process parameters and critical control points, which should be mapped and identified on a process flow chart. Development data or a scientific rationale is required to support the critical process parameter selection. Risk evaluation models can be used to determine the critical control points.

It is also necessary to identify the "edge of failure"--beyond which predictions of product performance are uncertain--in order to keep the process consistently within expected ranges without spending more time than necessary on cleaning. This step results in the most efficient cleaning cycle.

Additionally, analytical test methods must be developed to prove that cleaning has achieved the target requirements. The most efficient path to development of a successful cleaning program will leverage existing knowledge and processes in order to minimize redundant efforts and streamline the development process.

Finally, all of the above should be included in a comprehensive development report.

To be defendable, the rationale for validation must be based on defined processes for the product, equipment and facility and all their associated variables. The cleaning process validation master plan should demonstrate an understanding of all federal, state and local regulations related to the activities of the cleaning process. This includes the EPA, OSHA regulations regarding chemicals and effluents related to the process, as well as FDA regulations regarding the effectiveness of the cleaning.

For the sake of simplicity, it makes sense to take a "family" approach for similar types of equipment and facility spaces, as well as for products with the same or similar target entities. In developing the master plan, it is important to consider (and document) a method for determining when more science is required for validation and when common sense is sufficient. Ultimately, the organization's risk tolerance will determine the answers.

The master plan also must document how the selected analytical methods are validated, and it must outline roles and responsibilities for cleaning and validation.

In developing the plan, it is important to define the minimal prerequisites for the cleaning process so that cleaning validation can be successful. The elements described above provide a starting point for determining whether a cleaning process has been defined to the point that it can be validated and that it meets the company's goals for production cycle times. If these key elements are not in place, it is not possible to achieve an effective and compliant cleaning process and subsequent validation.

Experience shows that defining the preliminary process elements is the largest part of the project. Once they are clearly defined, developing the cleaning validation protocol is simply a matter of identifying a sampling protocol that uses an approved cleaning procedure and test methods.

The bigger picture: looking beyond GMPs

The GMP elements described above are of utmost importance. They drive the foundation of the cleaning validation or, for that matter, of any technical project within an FDA-regulated industry. The successful project leader, however, also must address some other critical areas, including safety, environmental concerns and supply chain management.

For example: protecting personnel. The company has an ethical and legal obligation to safeguard its people from harm. Any industrial site must follow appropriate OSHA regulations, and part of the development of the cleaning process is ensuring that the process is safe. To do so, the site should employ the services of someone who is trained and educated in the area of safety and safety regulations. This person should perform an initial audit of the process, delineating safety concerns in detail as well as the resolution of any safety anomalies.

The safety expert's recommendations must be incorporated into the designs of the cleaning equipment, the cleaning process, the protective gear, the material flow, and the personnel flow and activity. The safety expert should perform a similar audit at the completion of the validation effort to ensure that the process has not strayed outside the real of safety regulations. Once the process is deemed safe, it can be available for routine implementation.

Watching wastewater: Many validated cleaning procedures incorporate the use of detergents and cleaning agents that may be detrimental to the bacteria and other microorganisms that consume organic matter in the wastewater treatment plant downstream of the site. The wise cleaning validation project manager will facilitate the assessment of the clean process effluent to ensure that it meets EPA requirements as well as any applicable state and local environmental regulations.

To accomplish this, the cleaning process should include measures to neutralize the pH of the outgoing water stream. This piece of the engineering puzzle should be addressed at the beginning of the project and designed into the equipment and process chain of events. It makes sense to validate the effluent neutralization step, although this is not a GMP requirement. It is beneficial to ensure the effectiveness and repeatability of this step, as it will ensure compliance with environmental laws and help position the company as an environmentally responsible organization.

Enhancing efficiency: The cleaning validation project can have a major impact on supply chain management, including its subset, manufacturing resource planning (MRP) or enterprise resource planning (ERP). The project's impact is potentially the greatest in the areas of materials management and capacity management.

The need to manage the cleaning detergent is a materials management issue. The project team must embark on a series of tasks in order to manage the detergent successfully in the site's inventory and raw material systems. First, the team must identify the detergent to be used in the operation. Next, the team must assign the detergent a code number and create an MRP item master that is compatible with the site's inventory system. Quality control testing specifications must be established, and analysts must be trained on the testing procedure.

Capacity management also benefits from attention during the cleaning validation project. One of the beautiful results of a well-run validation exercise is that is can yield a tremendous amount of data that can be used to quantify the equipment cleaning and preparation unit operation.

Every cleaning cycle that is validated supplies the site with data that can be associated with each batching vessel or piece of equipment that is to be cleaned. If the validation reports, SOPs, cleaning cycles, equipment and product are appropriately connected, it is possible to calculate labor, time and detergent consumption based on the production schedule for the year. Doing so will provide excellent data for budgeting and resource scheduling, as well as for measuring the capacity utilization of the unit operation. As a result, management can rely on quantifiable data, rather than estimates, to orchestrate the area. The process is simple, and the project manager can incorporate the exercise into the cleaning validation project plan.

For example, suppose a site a validated a cleaning cycle for its 200-liter stainless steel tanks, which the company uses for only one of its products. The company will produce 100 batches of the product in a year, and it uses one tank per batch. In addition, the project summary report states that the following cycle is validated:

1. Charge the tank with 100 L of water for injection (WFI).

2. Add 1 L of clean-in-place (CIP) detergent.

3. Attach recirculation loop per SOP "X."

4. Heat the solution to 80 degrees and recircluate the solution for 90 minutes.

5. Drain solution.

6. Charge tank with 100 L of WFI.

7. Recirculate the WFI for 10 minutes.

8. Drain solution.

9. Charge tank with 100 L of WFI.

10. Recirculate the WFI for 10 minutes.

11. Drain the solution.

12. Dry the tank with filtered air for 20 minutes.

It is possible to calculate the annual consumption of WFI and detergent, as well as the approximate number of hours that the site will need to dedicate to equipment cleaning, based on the information known about the cycle and the production schedule. In this example, WFI usage will equal 3,000 liters annually, and detergent usage will equal 100 liters per year. 100 batches per year X 300 L WFI per batch = 3,000 L WFI annually. 100 batches per year X 1 L CIP per batch -100 L detergent annually.

Conclusion: Real-world consequences

The concepts presented here are not revolutionary, but all too often organizations neglect to apply them--sometimes with dire consequences. At one site, for example, an operator who was following a validated cleaning procedure was blinded for several hours when the pH 12 cleaning solution he was using splashed and hit him in the eye. The injury could have been avoided had the cleaning procedure he was following instructed him to wear goggles and protective gear and to perform the tasks with another person present. In another case, an operator cleaned the hatch gasket on a tank by allowing the highly alkaline cleaning solution to overflow in an uncontained manner.

The spill contaminated exposed pallets of raw material in the adjacent storage areas. Although the employee was being diligent, he did not understand the consequences of his actions. Had the company had an internal safety expert reviewing the cleaning process, the unsafe condition might have been avoided

Another company caught the at of the EPA and local environmental regulators when the site discharged its pH 12 cleaning solution directly into the city wastewater system. The company could have avoided the problem--and the fines--by designing a neutralization unit operation downstream of the cleaning process.

Yet another company performed its GMP responsibilities admirably and released the new, validated cleaning cycles to the appropriate operations. After a week, equipment was backed up because site personnel could not clean it fast enough.

In today's lean, mean pharmaceutical marketplace, companies need every advantage to gain an edge over the competition. To that end, the savvy project manager will consider areas within the organization that are impacted by, and can be incorporated into, the cleaning validation project, in order to support overall operational success and not just GMP compliance.

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Critical Success Factors for a Cleaning Validation Master Plan

Some key items that the project manager should include in a Cleaning Validation Master Plan:

* Regulatory references

* Process development report requirements

* Analytical method requirements

* IQ, OQ and PQ requirements for equipment and systems

* CIP system validation

* Manual cleaning validation requirements

* Acceptance criteria/specification rationale

* Clean hold time validation requirements

* Micro-testing requirements

* Minimum number of successful sequential runs required for consistency

* Record times, temperatures, volumes, sequences (run approved process at worst-case end of ranges as applicable)

* Operator qualification and training requirements

* Protocol & Summary Report requirements

* Re-qualification program requirements

* Sustainable deliverables

Editor's note: Andy DiFelice, Technical Director and Senior Consultant, IPS, spoke at a Nov. 14 Expertbriefing titled "Cleaning Validation Critical Success Factors."

By Andy DiFelice and Chuck Stock, Integrated Project Services (IPS)