Introduction
Pharmaceutical companies should create and follow a standard operating procedure by implementing a cleaning validation to ensure future patient safety. Validation has received great attention by the FDA in recent inspections. Manufacturers must validate their cleaning process to ensure compliance with GMP regulations 1. One of the main keys in the manufacturing of dosage formulation is to develop cleaning procedures that will remove all types of residues from the equipment and containers. The goal of Cleaning Validation is to ensure effectiveness in cleaning equipment, and to prevent pollution and cross contamination of drug products to ensure the quality, safety; efficacy and potency are not impacted by inadequate sanitation procedures.
However, what are the direct ramifications of cross contamination and offenses for not implementing a cleaning verification and validation process? Inadequate cleaning can lead to adulteration of pharmaceutical products through the addition of other unintended matter or microbial contamination; this can result in serious repercussions, including death by those who ingest said contaminated pharmaceuticals. Continuous validation review ensures safety, quality, efficacy and purity of a product. Correction of potential problems, previously unsuspected, which could compromise the safety and efficacy of drug products, is essential 2. Cleaning Validation can implement a more modern risk management plan and quality control system on an employee level and help pharmaceutical companies benefit corporately on a local perspective. However, is validation review by an FDA auditor enough? Can there be flaws in such reviews that do not help a pharmaceutical company, because no repercussion or punishment was handed down? A review of the process the FDA uses can offer suggestions and insight into verification, validation and whether its process can benefit a pharmaceutical company and promote less recalls.
Validation and Verification
According to the FDA, “Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use.
This principle incorporates the understanding that the following conditions exist:
• Quality, safety, and efficacy are designed or built into the product.
• Quality cannot be adequately assured merely by in-process and finished-product
inspection or testing” (2- 4).
In other words, does the product meet the specifications? For example, the company must check they have developed the right product for their target market, which meets consumer needs and intended use. Validation is conducted to demonstrate that the device safely and effectively achieves a clinical benefit for an intended consumer population.
Verification, according to the FDA, is a confirmation by examination and provisions of specified requirements of validation have been fulfilled. In other words, do the output requirements meet input requirements? Verification is used to determine if specifications are met; for example, one must examine whether a company has developed a product by implementing the right process. Verification only needs a single unit evaluation and will always be based on a verification plan. This verification plan can be integrity tests, performance tests regards to samples, and so on. The verification plan is to make sure outputs meets inputs requirement.
Where validation typically involves testing and assures the specifications to be met, it usually takes place after verifications are completed. Validations are in place to create a finished product that is safe and effective for the intended consumer use. Therefore, the verification testing insures the product is safe and effective before approval through multiple testing on multiple patients.
Cleaning Validation:
Cleaning validation in a pharmaceutical active ingredient area should be the same as those implemented by the FDA in a pharmaceutical production area, and the objectives of equipment cleaning should be at a high standard. In both areas, this is mandatory to avoid contamination of a future batch with the past batch material. Cleaning validation insures there is no contamination from the equipment and containers; it provides a high degree of assurance to validate the performance of the cleaning process. In their December 2008 regulatory guidance, the Health Sciences Authority stated that, “cleaning procedures must strictly follow carefully established and validated methods of execution (2, 16, 59). This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients.” No matter what the circumstance, cleaning validation processes have to be planned and carried out in a way that contamination is reduced.
The first thing a drug company must do is pay attention to the objectives of the validation procedures. Based on warning letters cited, many pharmaceutical companies have failed to establish such objectives; even though validation should occur before product begins, and should prove the cleaning efficiency. Of those pharmaceutical companies cited, in warning letters, it is not unusual to visually discover that manufacturers use extensive sampling and testing programs following the cleaning process without ever genuinely evaluating the effectiveness of the steps used to clean the equipment. Cleaning validation is essential in securing an effective cleaning process; therefore, a keen eye is essential in this matter. The main reason for clean equipment is to prevent tainting of drug products, malfunctions or contaminations.
It is important to follow FDA regulations in terms of the cleaning process for the following reasons:
- Compliance Perspective: this creates an impurity free product, and is a key element in the process of any product stage from research, development and production.
- Microbiological Contamination: Improper cleaning and maintenance of equipment will lead to unintentional microbial growth or contamination; precautions are to be taken.
Validation of Sterilization Process:
For purity of sterile drug products, the equipment surface that comes in contact with containers, closures or drug product, should be sterilized. Similarly, it is very important in sterile processing to verify the procedures used to sanitize or sterilize the equipment. Also, it is equally important to verify the process used to sterilize the product and its closures or containers. Sterilization of equipment should be maintained between different batches and formulation of different drug products.
Some drug products should be sterilized like injections, eye drops, and hemodialysis solutions. Some of the most common sterilization methods are moist heat, dry heat, steam, gas, and radiation. Selection of a sterilization method is based on the drug product.
- Moist Heat Sterilization:
The most preferred method for equipment used in aseptic processing, terminal sterilization of irrigation solutions, ophthalmic and aqueous injection preparations. This method is not suitable for dry or non-aqueous preparations.
- Dry Heat Sterilization:
Commonly used for pyrogenic removal of glass containers or bottles; also used for product containers and glasses used in aseptic manufacturing, as well as heat stable powders and liquids.
- Gas Sterilization:
This sterilization is meant for surface sterilization of powders. Gas Sterilization is also used in heat labile product containers.
- Radiation Sterilization:
Radiation is used in the sterilization of heat labile product containers and also dry drug products.
Regulatory Expectations:
Cleaning validation is directed by regulatory expectancies to make sure that residues from one drug product will not move on and contaminates the next product. An efficient cleaning program starts with a properly designed cleaning process, followed by validation and maintenance. Some of these ‘good, clear and concise’ manufacturing practices for cleaning validation and requirements are described below:
US Food and Drug Administration 21 CFR Part 211: Current GMP for finished pharmaceuticals
Sec. 211.67 Equipment Cleaning and Maintenance:
(a) Equipment and utensils shall be cleaned, maintained and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils used in the manufacture, processing, packing, or holding of a drug product.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in 211.180 and 211.182 3, 4.
Sec. 211.56 Sanitation:
(b) There shall be written procedures assigning responsibility for sanitation and, describing in sufficient detail, the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed 3, 4.
Subpart F--Production and Process Controls
Sec. 211.100 Written Procedures and Deviations:
- There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess; such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units, and reviewed and approved by the quality control unit 3, 4.
Cleaning Validation Requirements
The FDA believes pharmaceutical companies must provide a means for written documents detailing the cleaning validation processes used for equipment and surfaces. If pharmaceutical companies have one cleaning validation process for cleaning between batches and use another type of process for cleaning between product changes, the FDA requires the written report of the cleaning validation techniques used to clean equipment and surfaces; there must be a report for each individual cleaning process. In the same way, if pharmaceutical companies have one cleaning process for eliminating water soluble deposits and another process for non-water soluble deposits, the written report should address both cleaning circumstances and should be evidently clear how each given procedure is to be executed.
Major pharmaceutical companies can then designate certain equipment to be used for certain drug manufacturing processes, since these processes often yield lingering or gum-like deposits that require special, in-depth cleaning processes since the residue is difficult to remove. Any deposits from the cleaning process, such as cleaners and solvents also require cleaning and removal from equipment and surfaces. The FDA then requires a closing cleaning validation report, signed and approved by management that clearly states the cleaning process is valid. The facts gathered in the report should maintain and conclude that deposits have been omitted to an "acceptable level".
Important Cleaning Validation Factors
The pharmaceutical company must concentrate on the purpose of cleaning validation. Many pharmaceutical companies do not succeed in even developing a cleaning validation process or written reports. They then use general testing with samples taken for cleaning validation, and they ignore the data that should be used to determine the efficacy of the steps used to clean their equipment. Certain points should be addressed when implementing a cleaning process, such as:
- When is a surface or piece of equipment clean?
- Is it cleaned by hand?
- What is the result of hand cleaning a cleaner wash?
- How effective is a labor-intensive cleaning process from batch to batch and person to person?
These are important factors in deciding what type of cleaning validation process is appropriate for determining the type, style and means of cleaning various surfaces, pieces of equipment and what type of cleaning each drug requires, not only between batches, between different drugs. The pharmaceutical company must recognize the steps that should be used and those that are able to be excluded for the most effective methods for a positive outcome in a cleaning validation process. The company must then regulate each cleaning process for each surface and piece of equipment. If possible, each surface, per say, will have one process for cleaning; although, this will be contingent on the drugs being manufactured and if the cleaning is between batches or between different pharmaceuticals. Cleaning validation should begin with equipment examination, followed by sampling and testing ultimately accompanied by a manager approved written report.
Cleaning Steps
- Each individual company needs to perform an equipment examination to determine the type of cleaning processes to implement. Employees must be trained in individual cleaning processes of surfaces and equipment, and be knowledgeable on reports to be filed along with the cleaning.
- Management must examine the written report and cleaning validation process to regulate proper validation. According to the FDA, this includes “checking the flow charts and piping diagrams for the identification of valves and written cleaning procedures.” All hardware must be labeled and tagged for easy identification for, not only the auditor, but the employee cleaning the equipment. Hardware that is not properly labeled can, as a result, not be cleaned properly voiding the validation process.
- Employees should carefully reads labels and instructions during the cleaning process. The cleaning process should be followed down to the exact protocol, especially with time sensitive cleaning products that can leave deposits or harmful residue. There should be documentation providing proof that microbial proliferation is not present. Thus, surfaces and equipment should be hand or air dried, stagnant remaining on surfaces or in equipment prior to cleaning procedures can promote microbial proliferation and render the cleaning process invalid (59-61). This can cause harmful bacteria to grow thus contaminating entire batches, resulting in patient illness and sometimes death.
Sterilization
Surfaces, and especially equipment, are to undergo sterilization or sanitization processes to eliminate the possibility microbial spores. Thus, according to the FDA it is imperative that, “control of the bio-burden, through adequate cleaning and storage of equipment, is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility.” Management must make it well known to employees that sterile processing of surfaces and equipment within the validation of sterilization processes may not be adequate to successfully remove all microbial spores, pryogens and bacteria. Therefore, the strict adherence to the cleaning processes must be followed per piece of equipment and surface for insurance of proper cleaning.
Cleaning Validation Written Reports
Management must inspect all surfaces and equipment. Thus, specifying the way each cleaning process is to be validate. Each process should require specific documentation as to the amount of paperwork to be kept in specified log books. For instance, pharmaceutical companies can require batch records, in addition to batch records, log sheets that entail each step in the cleaning process should be filed an approved by management. The written reports for each cleaning validation process will vary since each surface and piece of equipment will likely have a different cleaning process for batches of the same drug and between processing different drugs. Thus, the length of paperwork will vary depending on the length and strictness of the cleaning process itself (59-61). More intricate cleaning processes will entail critical documentation, especially when cleaning machines that bulk process. Thus, the written reports should include the name of the employee who cleaned the equipment and a time stamp.
In regards to cleaning simple surfaces, it may suffice for the employee to simply log the cleaning process was completed with a time stamp since it simply needs to be documented on paper. Written reports should also include levels of deposits measured after a cleaning process was completed--if any, testing and sterilization sample levels after cleaning, and any other data that can aid in a more effective cleaning process.
Methods of Evaluation for Written Reports
Analytical Methods
Often residues, deposits and contaminants like pryogens and microbiologicals can remain on equipment. Written reports can help eliminate this repercussion and put in place an effective cleaning process. Management must regulate samples and testing in order to enlist an analytical method to identify residues, deposits and contaminants. A repercussion of not having a valid cleaning process can be small levels of residues, deposits and contaminants going un-detected. Not to say there is no deposit whatsoever after a cleaning process, but certain levels can contaminate batches that follow a cleaning process, thus producing an expensive recall of a drug or several within one pharmaceutical manufacturing facility. An analytical method should be put in place with testing and sampling methods; thus, showing written proof that residues, deposits and contaminants can be detected and removed from the surfaces and equipment used during processing.
Sampling
The FDA accepts two types of sampling. One being Direct Surface Sampling, and the other being Rinse Samples. Direct Surface Sampling is the preferred method when sampling for written records.
- Direct Surface Sampling – Management must run tests to determine what type of material should be used for effective sampling. Case in point, certain adhesives in testing swabs have been proven to interfere with the data collected during sampling and produce a negative sample. Sampling should have current data regarding a positive reading that will then validate the cleaning process. Positive effects of Direct Sampling that levels of residues, deposits and contaminants can be effectively monitored and measured in equipment with hard to clean areas. Thus, residues, deposits and contaminants that are impenetrable by a simple cleaning process can be sampled and removed for effective cleaning.
- Rinse Samples – Rinse samples can be most effective in the evaluation of cleaning processes in machines that are monetary and cannot be disassembled day to day. This is most beneficial to pharmaceutical companies who mass manufacture batches with large equipment. Unfortunately, rinse samples is that the residue, deposits or contaminants may not be soluble, thus a rinse will not produce any data for written record, rendering a negative test and sample reading. Management must implement and educate employees in examining equipment to test potential residues, deposits and contaminants, not just examine the equipment or the water left over from any residue.
Testing
Testing is often implemented in pharmaceutical companies to determine what needs to be done to create an effective cleaning process. This will help resolve what the best methods are to validate a cleaning processs. Tests are run until an effective, valid cleaning process is proved through data. Employees must test, take samples, and retest surfaces or equipment until deposit level is maintained as satisfactory under FDA requirements. Retesting and resampling should be done on an reoccurring schedule to document whether the cleaning process is valid or not; thus, maintaining a safe level of deposit, or this will help employees eliminate the presence of deposits that render a cleaning process useless, helping management re-structure cleaning processes until successful levels are maintained.
Cleaning Validation of Products Used in the Process
Employees must maintain records of detergents, solvents, soaps and products used in the cleaning process to show levels of possible deposits, residues or contaminants introduced to manufacturing processes by the cleaning process itself. Case in point, if a cleaning product is left behind on a piece of equipment this can cause a negative sample to be taken. Another problem can arise when cleaning products offer no chemical composition or list of ingredients used to create the product. Thus, there is no way the chemical compounds can be analyzed in testing data. Thus, pharmaceutical companies must meeting FDA regulations by using cleaning solvents and that are easily removed during the cleaning process; no residue should be left behind, thus the cleaning process is validated.
Repercussions
Recalls
Recalls are a direct result of cross contamination. Cross contamination can be prevented with the implementation of a cleaning process and removal of microbes, removal of pyrogens, and foreign matter through cleaning verification, filing of cleaning records and maintaining a clean environment per the requisite of the FDA. While cleaning procedures are much more stringent for sterile products, validation helps determine the cleaning procedures and verification is in place to ensure pharmaceuticals are not recalled.
Hospira Recall:
According to the FDA warning letter issued to Hospira Inc., “Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].57 For example, your firm failed to assure adequate process design and control of Liposyn, Propofol, and Cleviprex emulsion products, and present objectionable particulate contamination, primarily on stainless steel. Such controls would include, but are not limited, to appropriate component controls, equipment suitability, equipment maintenance, and filtration. This particulate contamination problem has been a persistent and serious issue at your firm for multiple years.”
Hospira Inc. voluntarily conducted a recall, because some of the containers may contain particulate matter; the particulate was primarily made up of sub-visible inert stainless steel particles. Based on the above information lack of documentation of process deviations, and proper validation of sanitation procedures and equipment maintenance, may lead to product recalls.
Teva Recall:
According to FDA warning letter issued to Teva pharmaceuticals, “Failure to maintain records for the cleaning and sanitizing of equipment [21 CFR 211.67(c)]. For example,
a) Your firm has failed to maintain records to document that the manufacturing areas and production equipment are exposed to sanitization solutions for the contact time of (b)(4) minutes. This requirement is described in the procedure entitled (b)(4)
Teva voluntarily recalled some of the lots of these emulsions due to lack of sterility assurance. The product was manufactured on equipment found to be contaminated with microbiological organisms.
Knoll Pharmaceutical Warning Letter
In the event of non-compliance the FDA reserves the right to file an injunction against a pharmaceutical company, perform a seizure of the pharmaceuticals and deny export approval requests for new drug applications and so on. The comparison to an actual letter found this to only be a warning in 1998. Case in point, the FDA inspector found residuals on various equipment after swabbing, and that seven different drugs were under FDA violation from an improper cleaning validation process. The pharmaceutical firm even released one of the three consecutive lots following a disqualified or failed batch 62 after the product failed three sampling and testing phases. The warning letter went so far as to claim the company’s cleaning validation process, as a whole, was ‘inadequate’. According to Bloomberg Business Weekly, Knoll Pharmaceutical is still in operation today, dispensing the same drugs that were mentioned in the warning letter.
Evidence
The evidence that cleaning verification is effective and creates a safe, non-contaminant environment can be analyzed through warning letters in which the FDA have identified companies who did not finish all necessary validations. In nearly 35 percent of cases, a lack of validation procedure was observed. Other validation related observations include a)11 of 55 are did not meet clean requirements, b) 14 of 55 show a lack of documentation in validation test specification, c) 11 of 55 exhibit a lack of batch variation controls, d) 11 of 55 show a lack of establishment of the reliability of the supplier’s analyses through appropriate validation of the
supplier’s test results, e) 9 of 55 display a lack of data with the efficiency of manual cleaning, f) 9 of 55 failed to validate those operations critical to the quality & purity of the active pharmaceutical ingredient, and g) 8 of 55 exhibit a lack of cleaning validation for procedures used.
Why are Violations Occurring?
Based on the above data, one probability is that observing validation as a regulation has not been a criterion for pharmaceutical companies. Thus, companies are losing the concept that implementing cleaning validations is a mandatory compliance, because there are no direct repercussions. Although it is important to meet specifications and requirements, companies with the mindset of seeing validation as a regulation and not as compliance, are violating simple cleaning validation procedures. People employed by those companies will result in viewing validation as a task that should be reviewed by their quality assurance team instead of valuable mechanism in their day to day duties, put in place by agencies like the FDA, to ensure their product is safe and effective for public; thus, putting the blame on a corporate level when it is a simple factory level problem that can be solved through cleaning validation.
Even when the pharmaceutical company implements a checklist, criteria require marking; the employee must be diligent in their attention to validation activities that will be necessary to satisfy quality control system or good manufacturing practices. While this path may aid in comfort of anticipated benefits, like good compliance or meeting the criteria of validation requirements, the employment work as a team to improve their chance of learning the value of validation. Implementing a ‘team player’ initiative within employees will have a positive effect on the assurance of cleaning validation in individual companies; violations will lower tremendously, and employers will see fewer recalls.
However, what if this is happening on a more global level? Often there should be ramifications in place. For instance, an auditor comes to a pharmaceutical manufacturing facility. The auditor then checks that the facility has been thoroughly cleaned; there is no evidence of cross contamination. The auditor then asks for the log books. The manager claims that the employees keep the area clean, but no log books are filed. The auditor does his official report and no ramification results from the pharmaceutical company not having the proper documentation. Often the offense is on the end of the auditor, and the reason no change or ramification is set is due to the inability of the auditor to properly report the negligence. Can there be a solution to this ongoing issue?
Solution
While following GMP’s to develop a passage between process controls, verification, validation and risk analysis, there is a necessity for good monitoring or tracking systems companies should use during quality control checks; if these quality control checks are followed throughout production and development, this system can provide an excellent field guide, and will insure all the necessary documents are completed and organized according the cleaning validation plan that the company has developed. The company must implement a verification stage. The verification stage is a key element and critical factor within the quality control process; a well-planned verification stage contributes a strong foundation for the validation stage. The verification stage will become a benefit in reducing market approval time by way of the results of cleaning validation.
On a global level, the FDA must also strengthen its audits. The cleaning verification and validation process then serves no purpose if no punishment is rendered by not following proper procedure, not properly filing logs and keeping records, which eventually could result in a mass law suit if the consumer of the pharmaceutical company has an adverse reaction or possible death occurs due to microbiological cross contamination, and the consumer has knowledge of said negligence. Therefore, can it then be assumed that the FDA should publish a thorough guide, much like the health department to alert the public of possible risks?
Conclusion
Although, the above-presented GMP violations are not an all overall list of inspectional observations, they are the most common citations recorded in the last 4 years. Based on the above evidence and recalls it is important to remember that lack of attention to these ‘good’ manufacturing practices and their specification criteria data is affecting the strength of the overall effort that pharmaceutical companies put in quality control system and good manufacturing practices. Additionally, the lack of quality control affects public safety indirectly. After reading the letter to Knoll Pharmaceutical confirming a warning for major contamination violations, knowing the company still released a batch of the contaminated drug, and is still in business today confirms that this process of inspecting a cleaning validation process is ineffective due to the release of a contaminated batch. Therefore, the FDA and its auditors should be liable for, in part, the safety of the public and what they are consuming in way of pharmaceutical negligence. However, in further finding these warning letters are effective, considering most of the pharmaceutical companies that receive violations are still in business, because they have proved implementation of a valid cleaning process after the warning letter was received. Thus, pharmaceutical companies should create and follow a standard operating procedure by implementing a cleaning validation to ensure future patient safety.
References
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- Hospira Announces an Expansion of a Nationwide Voluntary Recall of Certain Lots of Liposyn™ and Propofol That May Contain Particulate Matter
http://www.fda.gov/Safety/Recalls/ArchiveRecalls/2010/ucm213880.htm
- Teva Pharmaceuticals USA, Inc., Sellersville, PA, by letters on October 27, 2009 and October 28, 2009.
Manufacturer: Teva Parenteral Medicines Inc., Irvine, CA. Firm initiated recall is ongoing.
http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm193723.htm
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- Bloomberg Businessweek. (March 20, 2013). Company Overview of Knoll Pharmaceutical Company. Retrieved from http://investing.businessweek.com/research/
stocks/private/snapshot.asp?privcapId=1380112
