Compliance and Cost Competitiveness

Ø  Tablets and Capsules, Volume 10, Number 7 (October 2012)

Cleaning validation is a legally enforceable regulatory requirement that often draws investigators' attention during FDA inspections. This article, which focuses on manual cleaning of non-sterile solid dosage processes, describes how to approach cleaning validation to prevent cross-contamination.

Validating any process requires documented assurance that the process is capable of reliably and reproducibly generating the expected results. By this definition, Cleaning Validation must offer documented assurance that your cleaning procedures are reliably and reproducibly effective in reducing the levels of all contaminants, including the residue from previous products and the cleaning agents' residues; microbial contaminants must also fall below the specified limits, levels that are deemed acceptably safe. Can you imagine validating a process without fully understanding the process? Of course not! The same is true of Cleaning Validation. You must fully understand the cleaning process, in all its steps, to ensure that you can achieve effective Cleaning Validation. The FDA's "Guide to Inspections: Validation of Cleaning Procedures (7/93 )" [1] explains very well the regulatory expectations regarding Cleaning Validation programs.

Manual versus automated cleaning

Cleaning procedures must be written with as much detail and specificity as necessary to ensure reproducible and reliable results. That means clearly defining each staff member's responsibilities , details of the sequential steps involved in a cleaning procedure, and the frequency of cleaning. In FDA-regulated industries, be it food or pharmaceuticals, cleaning practices vary according to the nature of the processes involved-sterile versus non-sterile, and according to the dosage form: solid, semi-solid, liquid, or gel. Practices also vary according to how cleaning is performed: mechanized cleaning versus manual cleaning. Some companies use semi-automatic or fully automatic clean-in-place (CIP) systems to clean their equipment; others use the manual method, in which equipment is dismantled and the parts are brought to a designated area for cleaning out-of-place (COP). Manual cleaning poses far more serious problems than automatic cleaning in terms of standardization of the cleaning steps because it gives rise to numerous sources of inherent variability. In contrast, a mechanized CIP approach generally entails the use of instrumentation that gives you operational control and provides a more reproducible performance. Operators performing manual cleaning must therefore be well trained so they minimize the variability that is inherent to it.

Understand your facility's processes

When developing cleaning programs, focus on the nature of the manufacturing activities performed in the facility. The first important considerations are whether the facility manufactures one or multiple products and, if it makes several products, whether equipment is product dedicated or shared by different products. Ideally, only product-dedicated equipment should be used, which would reduce the degree to which product residue must be removed. This is especially helpful when the residues are sticky, tar-like, or otherwise difficult to remove. In fact, some equipment components like filter bags or cartridges and/or polymer-based gaskets and hoses-should be dedicated to single products, not shared. Next, understand the nature of the products you manufacture in terms of their therapeutic effect or toxicity, as well as their solubility in water and other solvents. That understanding will enable you to select suitable cleaning agents. Ideally, the cleaning agents themselves should leave no residue or an extremely minimal amount on the surface of the cleaned equipment. Furthermore, you should understand the composition of all cleaning agents so that you can reliably detect specific cleaning agent residues using validated analytical methods.

What to specify

Equipment-specific cleaning procedures should specify the extent of cleaning to be performed between successive batches of the same product and when changing from one product to another. Cleaning the equipment between batches of the same product-referred to as "minor cleaning" or "campaign cleaning" does not require Cleaning Validation, and "visually clean" is generally considered an adequate acceptance criterion . Nonetheless, the cleaning procedures must specify which parts to dismantle for cleaning. These instructions must also describe the steps required to ensure residue is removed, not just from product-contact surfaces, but from the surfaces of control panels, drive motors, etc. These surfaces are often overlooked because Cleaning Validation requires confirming removal .of contaminant residues from product-contact surfaces only. Even so, contaminants may still migrate to product-contact surfaces from non-product- contact surfaces, and those surfaces frequently draw investigators' attention during regulatory inspections. Thus, make sure your procedures provide clear instructions for cleaning the ceilings, walls, and floors of the processing rooms; they should also address how and when to change the filters used in the air circulation systems that supply clean air to the room. Also establish a sequence for cleaning the room and equipment so that the cleaned parts do not gather residue while you clean other parts in the same room. Your procedures must call for covering the cleaned pieces of equipment and placing status tags on them. Furthermore, the procedures must specify the steps to follow to prevent cross-contamination that could occur if pieces of equipment contaminated with residues of different products are cleaned in the same area. There should also be written procedures for cleaning the designated cleaning room to prevent cross-contamination there. All activities related to the use and cleaning of the cleaning room must also be properly logged. In addition, the cleaning procedures must address how to prepare the cleaning agent solution, including specifying its concentration and the temperature of the solvent used to prepare the solution. It is also important to specify the hold time, which denotes how long the cleaning solution may be kept and used after it's prepared. As you can see, cleaning procedures and the instructions for performing them must be very detailed. Thus, each cleaning step - including initial rinsing of dirty equipment, soaking the equipment in cleaning agent solution, rinsing off the cleaning agent, and giving the equipment surface a final rinse with purified water-must be defined with specifics. These include minimum duration of each step, temperature of the rinse and wash water, and whether scrubbing is required and, if so, the type of scrubber to use.

Accounting for variability

Clearly, you cannot specify these variables without knowing the range of variability associated with them. Consider, for example, a cleaning step that specifies rinsing the equipment surface for "X" minutes with hot potable city water. In that case, you would likely need to determine how the water's flow rate and temperature might vary according to how many other taps could be open while you're rinsing. The pressure of the water jets used for cleaning can also vary depending on the type of spray gun used, and that could affect cleaning effectiveness. The extent of these types of variations must be known before you start to validate your cleaning procedures. To begin, perform exploratory studies that establish the range of critical variables. In our example, study how opening a certain number of taps affects the flow rate and temperature of the water. What are the possible variations? Then use your observations to develop reliable cleaning procedures before starting the actual Cleaning Validation. Also keep in mind how long the equipment is kept dirty after the manufacturing process finishes and before cleaning starts. Typically, the more time that passes, the more difficult it will be to clean the equipment. The significance of this "dirty hold time" is obvious to anyone who has cleaned equipment used to make softgels. How the equipment dries or is dried after cleaning must also be studied. You need to understand the drying conditions and how long the cleaned equipment is stored so you can prevent the creation of an environment conducive to microbial growth. In short, "dirty hold time" and "clean hold time" are integral parts of the cleaning program.

Team work

The best cleaning programs are developed with the help of inter-disciplinary teams, and you should recruit members from manufacturing, maintenance, quality control, validation , and Quality assurance. It is also paramount that you involve the operators who will perform the cleaning. They should participate directly in developing the cleaning programs. You'll find that their hands-on experience is a great help in identifying and addressing sources of variability.

Lifecycle approach

In its "Guidance for Industry: Process Validation: General Principles and Practices" [2], the FDA recommends a lifecycle approach that can also be applied to Cleaning Validation (Table 1).

This concept of validation as a continuous process that comprises distinct stages also aligns with the lifecycle approach outlined in the FDA- ICH's guidances, namely "Q 8(R2 ): Pharmaceutical Development" [3], "Q 9: Quality Risk Management" [4], and "Ql0: Pharmaceutical Quality System" [5]. Applying a lifecycle approach to Cleaning Validation helps you adopt technological advances and other innovations. According to the lifecycle approach, Stage I of Cleaning Validation should focus on defining the specific requirements and developing the steps necessary to reliably and reproducibly meet cleaning requirements. Thus, as discussed above, you begin by identifying sources of variability and develop systems to minimize their effects. Stage II of Cleaning Validation involves performing the actual Cleaning Validation to gather documented, scientific evidence about the effectiveness of the cleaning procedures that you developed in Stage I. Although a detailed discussion of the Cleaning Validation process is beyond the scope of this article, some critical aspects of the program involve developing validated analytical methods. These methods must be capable of quantitatively identifying residues of specific contaminants on the equipment surfaces. Direct surface sampling - typically by swabbing - is generally preferred over rinse sampling, because direct surface sampling is more effective in collecting residue samples, especially from surfaces that are difficult to clean, such as the innermost part of a narrow pipe. Direct surface sampling is also more effective in collecting residues that may have dried on the equipment surface. Acceptance criteria for the residue carryover limits must be scientifically established, and the materials of construction and the exact locations of the equipment surfaces to be swabbed must be defined and depicted using photographs in the Cleaning Validation protocol. Stage III of Cleaning Validation is intended to provide ongoing assurance that the Cleaning Validation performed during Stage II remains effective. This continuous performance verification requires documented assessment o any changes in the cleaning agent, as well as any cleaning procedures implemented after Cleaning Validation was executed. Most companies perform periodic cleaning verification runs to confirm the validity of their Cleaning Validation, even if no major changes were made after Cleaning Validation was completed.

Compliance is good business

The overall objective of Cleaning Validation is to prevent cross-contamination by minimizing surface contaminants, including residue from previous products, cleaning agents, and microbes. Any product manufactured under risk of cross-contamination is considered adulterated, legally speaking. Thus, successful Cleaning Validation is imperative to ensuring the identity, strength, Quality, and purity of the drug product, 21 CFR Part 211 requires [6]. Effective Cleaning Validation is necessary not only to meet regulatory requirements, but to succeed in business. After all, ineffective cleaning programs and inadequate Cleaning Validation may cause cross-contamination that poses health hazards to patients, who are your ultimate customers. Poor cleaning and ineffective Cleaning Validation may also result in huge economic losses due to the time and other resources you spend conducting investigations related to cross-contamination. The extent of the adverse impact of cross-contamination on a manufacturer's reputation among patients and medical professionals, the loss of business opportunities, and above all, the risk of regulatory action against the manufacturers cannot be overemphasized. Strive for effective and compliant Cleaning Validation. It is both a regulatory requirement and a sound business goal. Make sure the validation is scientifically sound, and make sure it includes verifying the effectiveness of your existing cleaning programs.

References

1. 1. 1. 1. "Guide to Inspections: Validation of Cleaning Procedures (7/93 )," FDA Inspection Guide (July 1993).
         2. "Process Validation: General Principles and Practices," FDA's Guidance for Industry (January 2011 ).
         3. "Q 8(R2 ) Pharmaceutical Development," FDA/ICH Guidance for Industry (November 2009).
         4. "Q 9 Quality Risk Management," FDA/ICH Guidance for Industry (June 2006).
         5. "Q 10 Pharmaceutical Quality System," FDA/ICH Guidance for Industry (May 2007).
         6. Title 21 - Food and Drugs, Part 211 "Current Good Manufacturing Practice for Finished Pharmaceuticals

Parveen Bhandola, Ph.D., ASQ CQE is director of validation and process improvement at Nostrum Laboratories, Kansas City, MO. The views expressed in this article are the author's alone and do not necessarily represent the views of his employer or any other organization. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it..