Automated Cleaning Validation Systems: Regulations, Repercussions, and Resources
Whether you are a startup pharmaceutical/device manufacturer or a large Fortune 500, PhRMA–represented 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.
It is the goal of this article to guide the reader, no matter what his or her current level of knowledge, through the general background and importance of cGMP along with the specifics as they pertain to automated cleaning validation systems. We’ll 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. Let’s begin.
2.Intro to cGMP
“Current Good Manufacturing Practice” is a set of regulations that extend from the International Conference on Harmonization (ICH)[i] 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. (In the United States, such approval comes through the FDA.)
cGMP, although written into the 1938 Food, Drug, and Cosmetic Act (FD&C), did really not gain traction until the 1962 Kefauver-Harris Amendments to the FD&C. In the amendment, a drug is deemed adulterated if,
“The methods used in, or the facilities or controls used for, its manufacture, processing, packaging, or holding do not conform to or are not operated or administered in conformity with cGMP to assure that such drug meets the requirements of this Act as to safety and has the identity and purity characteristics, which it purports or is represented to possess.”[ii]
Fast-forward to the present day regulatory system: The current GMP regulations are a culmination of evolving amendments and alterations. The FDA, after the 1978 adoption of the Medical Device Amendment, began to merge the drug GMPs with the requirements set for medical devices (also known as International Organization Standards, or ISO). That’s not to say that medical devices and drugs share all the same regulations; the Quality Systems Regulations (QSR) for medical devices[iii] were instituted in 1996 by the FDA.
Lately, several guidelines have been published by the FDA to assist the manufacturing quality team to actively address cGMP. I’ll list them here and although we won’t 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
- 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 guidelines exist on the FDA’s website (fda.gov) and anyone who works within the pharmaceutical/device industries should know of the general guidelines, but I list the last guideline 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 we’re here: Cleaning Systems and their validation.
- a.Type of Cleaning Systems
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.”[iv]
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. Such families involve only the equipment for manufacturing similar products that are cleaned by the same or similar cleaning processes.
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 into equipment families must be justified and documented in SOPs. Later on, these kinds of grouping will help to simplify cleaning validation.
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.[v]
The duration between the end of equipment cleaning and the start of subsequent operations (e.g., autoclave, sterilization-in-place [SIP], or production usage) is called clean hold time. Following cleaning, equipment to be reused should be stored to protect it from contamination. Storage instructions are specified in a SOP that delineates the cleaning procedure and/or the storage procedure. The SOPs created should also define the equipment’s storage conditions, storage expiry and the rationale for each.ibid
All of the SOPs related to grouping of equipment and its storage will be analyzed in the Cleaning Process Validation procedures. The rationale for the revalidation frequencies should be appropriately documented and justified then tested, yet again, via validation.
In its most general sense, process validation is comprised of three individual qualification categories:
- 1.Installation Qualification (IQ),
- 2.Operational Qualification (OQ), and
- 3.Performance Qualification (PQ).
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. Hence, cleaning process validation is part of the PQ process validation category.
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. what’s 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 or 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 specialist’s most invaluable partner.[vi]
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”.[vii] The FDA 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 inspector’s checklist will be the manufacturer’s SOPs that 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 (this should be stated clearly as part of the SOP) and determine 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 stated and be detailed enough that a person working for a substantial amount of time will know how to follow the protocol in the SOP. This point leads us to personnel: Any and all personnel working with the cleaning process should know the SOP in great detail and should be able to demonstrate their knowledge to the inspector. Documentation of training will be a critical part to the SOP tracking.
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. Such attention to detail will be well received by the agency and will demonstrate leadership within the pharmaceutical industry. Remember that the inspector will, at least internally compare the company’s processes with what other companies of the same ilk do; so it goes without saying that the validation specialist should be aware of industry standards, if any.
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 to have established methods and stop-gap procedures to ensure product safety and integrity. One may never be able to achieve perfection, but nevertheless, perfection should be the ultimate goal.
5.Deviations and their Repercussions
So what happens when “less than perfection” occurs? What are some of the repercussions from cleaning validation errors and transgressions? The answer is one of or a combination of many actions can occur. We’ll discuss these items here.
The FDA representative producing a Notice of Inspection, otherwise known as a Form 482, as discussed above initiates the inspections. 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).[viii] 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. The warning letters will be extremely detailed and will typically have excerpts from files, drug lots, validation logs and the like. 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. In a statement to the press, the then deputy director of the FDA Eric Blumberg said,
“The agency has allowed itself to get into this situation of issuing warning letter after warning letter to the same company, without taking any action. [With this ruling, the FDA has tried to send the message out that that’s not going to happen anymore.]” [ix]
The aftershocks of the previous case rang through the entire company with the President and Chief Operating Officer resigning their posts. Unfortunately, they are not alone. The president of another company was found liable for GMP violations when, in the ruling of United States vs. Park, the CEO was found responsible for storing food in a warehouse under unsanitary conditions. These cases go to show that no one is above the regulatory authority of the FDA and therefore, everyone has a stake in creating, implementing and improving upon cGMP and, as it applies here, cleaning validation processes.
After reading the above commentarie you may have begun to feel a bit inadequate when it comes to handling cGMP at your facility. Or perhaps you know of holes in your processes that have to be filled, but are unsure as to how to handle it or who and when to ask for assistance.
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. A company needs a forensic toxicologist to help them analyze data regarding liver toxicity: CRO X has ties to just such an individual. A device manufacturer is unsure about the material production in the latest iteration of an approved device: CRO Y has just completed a similar project with a materials engineer who really understands FDA device regulations.
It is this flexibility that is most valuable to the modern pharmaceutical or device manufacturers. Each CRO team member is highly versed in the FDA regulations, has intimate knowledge of the FDA’s 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) is an expert regulatory consulting group that can help you with all of the details of your cleaning validation system. We are 'the experts to work with' for drug regulations in the United States and Canada. We also work extensively in Europe and Asia. You may contact us at: www.regaffairs.net or call us at 248 747 8008 and ask for Stephen Goldner. With more than 30 years of experience getting drugs and medical devices approved, let us show you how to comply with the regulations cost effectively and with common sense.
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.
 Modern regulations surrounding devices did not exist until 1978 when devices were included within the FD&C under the Medical Device Amendments.
[i] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients: Q7
[ii] Federal Food Drug and Cosmetic Act. Section 501 (a)(2)(b) or [USC Title 21 Section 351 (a)(2)(b)
[iii] 21 Code of Federal Regulations Part 820
[viii] Pisano DJ, Mantus DS. FDA Regulatory Affairs: A Guide for Prescription Drugs, Medical Devices, and Biologics. ©2008 Informa Healthcare. New York, NY 10017. P. 235
[ix] Goldfarb, N. Schering-Plough GMP Consent Decree Puts Drug Industry On Notice. Food and Drug Letter. 2002. http://brucegoldfarb.com/FDL1.pdf
Written by: Jessica Knowlton, MS CRA
May 4, 2012