By Jessica Knowlton

Automated Cleaning Validation Systems: Regulations, Repercussions, and Resources

Whether you are a startup pharmaceutical/device manufacturer or a large Fortune 500, PhRMArepresented company, the quality control staff who works with you understand the obstacles associated in following the regulations for current Good Manufacturing Practice (cGMP). Behind every carefully-constructed standard operating procedure (SOP) lies the chance for unknown errors, the results of which can materialize into any combination of facility shut-downs, product seizures, fines and criminal actions. Cleaning validations systems, which have their own specific regulations, are no different.

This article will guide the reader through the general background and importance of cGMP along with the specifics as they pertain to automated cleaning validation systems. Well then conclude with sections on the repercussions of cGMP breakdown and when to ask for expert help, because knowing that you are in over your head is the true mark of a competent quality control manager.

Current Good Manufacturing Practice is a set of regulations that extend from the International Conference on Harmonization (ICH) guidelines and govern, the manufacturing of drugs, biologics, and devices, whether they are to be used for human or animal consumption. The aim of this set of regulations is to ensure that the final manufactured product is unadulterated, meaning that the identity, quality or purity of the item has not changed from the government-approved formulation or design.

Lately, several guidelines have been published by the FDA to assist the manufacturing quality team to actively address cGMP. Ill list them here and although we wont touch on their contents, it would behoove the quality manager at any manufacturer to be intimately acquainted with each:

Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach

CGMP for Phase 1 Investigational Drugs

Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations

PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance

Process Validation: General Principles and Practices

Of course, many more guidances exist on the FDAs website and anyone who works within the pharmaceutical/device industries should know of the general guidances, but I list the last guidance on Process Validation specifically because it is apropos of the continuing discussion here. With this in mind, we should begin our discussion of the real reason were here: Cleaning Systems and their validation.

Cleaning systems assist the manufacturing facility in transitioning between the manufacture of (1) different pharmaceutical products or (2) different batches of the same pharmaceutical products. In their December 2008 regulatory guidance, the Health Sciences Authority stated that,

Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients (APIs). In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level.

The employ validation, the company must first understand what equipment it has. Cleaning equipment is typically grouped into equipment families based on equipment design, construction material, geometry, complexity, functionality, or cleaning procedure. Grouping may also apply to equipment that is cleaned by an automated clean-in-place (CIP) process, a semi-automated CIP process, a manual cleaning process, or an automated parts washer.

Grouping may involve separately validating the extremes of a group (e.g., the largest and smallest portable tanks in a group), or it may involve testing only the worst case in a group (e.g., the most difficult to clean transfer line). The company should examine each of their production parts and assess their grouping in both categories, and document their rationale for such in a SOP.

The purpose of cleaning systems validation is to demonstrate that equipment which has been cleaned can be safely used for manufacture of another product (or another batch of the same product). More often than not it is impractical, especially for major pharmaceutical companies, to clean all of the production equipment individually. Instead the company, working with a team of validation specialists, determines a process that might adequately perform the cleaning using either automated or manual cleaning. The cleaning process performance is then validated or, verified that is it reliable and repeatable based on the written SOPs and government-instituted levels of particulates.

The specifics of cleaning process validation revolve around the many regulations set forth through the FDA and other health agencies. Validation is also based on factors such as product solubility, toxicity of the product or its degradation components, the individual components of the manufacturing system (i.e. whats the hardest part to clean?), and possible interactions with the next type of drug to be manufactured.

The manufacturing company will also have to know how to identify residues and limits to identification, known residue acceptance criteria and who has ultimate control on the levels (e.g. EPA? FDA?) and how to sample the wash materials for those residues. When one begins to think about all of these things, it becomes very clear the minutiae that are involved. Needless to say, an expert in toxicology will become the validation specialists most invaluable partner.

All definitions about cleaning validation and the requirements involved in the process aside, it behooves the validation specialist to understand how the FDA and/or their representative sees the site it inspects. Here, we will discuss the inspection of cleaning validation processes as seen through the eyes of an inspector.

The FDA has published a Guide to Inspections Validation of Cleaning Processes. In reading this document, one can see that the agency is very aware of the importance of inspections and the ramifications from inadequate procedures. Several such cases are listed within the Background section of this document as examples of things that may happen should a breakdown in the cleaning process or general non-compliance occur.

Upon review of the validation process, the first item on an inspectors checklist will be the manufacturers SOPs which will need to detail the cleaning process for each piece of equipment. If different processes are used between two different batches of finished product, each of those processes will be expected to be detailed differently.

Additionally, and most importantly, the inspector will want to know how a manufacturer validates these processes and provide evidence that testing has occurred. This takes the form of a final validation report in which the management states that the process is valid.

Because validation includes testing of the process, the inspector will review sampling techniques and whether surface, rinse or other types of sampling are utilized.

The inspector will look at the objective of the cleaning process and the number of cleaning processes for each piece of equipment. The inspector will then examine the design of the equipment and whether they use automated or manual cleaning. SOPs that are written for the processes should be clearly written and be detailed enough that a person working for a substantial amount of time will know how to follow the protocol in the SOP.

Analytical methods that detect residuals or contaminants should be adequately spelled out. The validation specialist should also be well-versed in the latest technology that is used for detecting said residuals.

All of these items point to the fact that the FDA expects the validation team to really understand the systems they use, to have thought of the things that can go wrong and have established methods and stop-gap procedures to ensure product safety and integrity.

The inspections as discussed above are initiated by the FDA representative producing a Notice of Inspection, otherwise known as a Form 482. When the inspection is completed, the inspector presents his/her findings (if any) to the validation group and any senior officials within the company and concludes this meeting with a form that details the Inspectional Observations (Form 483). This is presented here as someone of a cursory interaction: the inspector visits, they perform their job function and present their findings. However, the receipt of a Form 483 is not ever to be taken lightly.

The information from the Form 483 is used to create an Establishment Inspection Report (EIR) that is reviewed internally by the FDA, and then classified as either:

No Action Indicated (NAI) – No Substantiative GMP Non-compliance,

Voluntary Action Indicated (VAI) – Substantiative cGMP Non-Compliance, but no further regulatory action required, or

Official Action Indicated (OAI) Further administrative and/or judicial regulatory actions are required.

Actions that can be taken by the FDA after findings of non-compliance can range anywhere from the sending of a warning letter to the company which states specifically which regulations the company is violating. A response, expected within 15 days, is a must and should absolutely address each and every transgression in great detail, explaining corrective actions that will be taken by the company.

The FDA is also within their rights to show up, unannounced even, and proceed to haul materials away from manufacturing sites if the agency feels that the company is not paying attention or if they feel patient safety is in jeopardy. If the product or process in question is part of an application such as an IND, IDE or the like, any and all trials can be halted immediately which, in turn, pushes the marketing of the drug back thereby costing the company millions of dollars in expected revenue.

Though one would imagine that only the smaller, less experienced companies would be more frequently guilty of cGMP non-compliance, it is not always the case. Schering Plough paid a fine to the tune of 500 million dollars as part of a consent decree for cGMP violations in their facilities based in New Jersey and in Puerto Rico. Additionally, the approval of Clarinex was delayed by about one year. This case was especially interesting because the FDA had sent several warning letters to the company previously.

After reading the above commentary you may have begun to feel a bit inadequate when it comes to handling cGMP at your facility. For decades now, pharmaceutical, biologic and device companies have been utilizing the specialized experience contained within contract research organizations, or CROs. CROs are specially designed to function as a catch all as they frequently employ expert consultants on a per project basis.

It is this flexibility that is most valuable to the modern pharmaceutical or device manufacturer. Each CRO team member is highly versed in the FDA regulations, has intimate knowledge of the FDAs inner workings and has working knowledge of how to phrase things to the liking of the agency. From the first draft of an SOP to the response for a Form 483, companies need the specialized individuals at a CRO who can translate their years of experience into practical and professional documents.

REgulatory Affairs Associates (RAA) can help you with your validation needs. We have 30+ years experience and our experts have worked with the FDA, Health Canada. and in Europe and Asia.

In conclusion, the handling of Cleaning Process Validation can seem like a daunting task, especially with all of the regulations to abide by, the SOPs to draft and the actual validation to assess. However, having a professional CRO by your side walking you through each stage of the operation will ensure a successful GMP program and build a platform for safe drug or device creation.

About the Author: Jessica Knowlton is a medical specialist and works for RAA (REgulatory Affairs Associates). Our URL is:

regaffairs.net

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