Requirement for the Manufacture of Drugs concerning Public Safety
The study will focus on pharmaceutical companies’ standard operation procedures. More in depth, the study will determine if cleaning validation and verification is a successful way to keep the quality of manufactured drugs at a high standard. The importance of the validation of a sterilization process will be examined. The study will list reasons for validation of sterilization through a set of regulatory expectations put in place by the FDA.
The regulatory expectations of the FDA will support the methods and analysis used to conduct this study. The study will also examine the success and failure of cleaning validation through cleaning validation factors, cleaning process steps and cleaning process written reports. This will be followed by a review of the violations of an invalid cleaning process through warning letters issued to several pharmaceutical companies by the FDA. The results will show several companies are in violation of FDA regulations. The study will then offer solutions to this ongoing problem.
Cleaning processes are used in pharmaceutical companies in order to ensure pharmaceuticals are manufactured without adulteration. In recent years, the subject of cleaning validation in active pharmaceutical ingredient manufacturing plants has received a large amount of attention from regulators, companies and customers alike(apic.cefic.org, 1999). There are many literature reviews that can validate the many reasons for implementing a cleaning process, validation process and verification process, as well as regulations set in place by the FDA. However, not all pharmaceutical companies manufacture the same drug. Also, they often use the same equipment for several different drugs. For that reason, each pharmaceutical company must take each individual situation into consideration in order to determine their need for validation.
Pharmaceutical companies must create and follow a standard operating procedure based on cleaning and sterility validation procedures to ensure future patient safety.Validation has received attention by the FDA in recent inspections, to ensure compliance with GMP regulations(Bloomberg Businessweek, 2013). One of the main keys in the manufacturing of drugs is to develop cleaning procedures that will remove all types of adulterants from the equipment and containers, and prevent contamination. The goal of cleaning validation is to ensure effectiveness in cleaning and sterilizing equipment, and to prevent adulteration and cross contamination of drug products to ensure the quality, safety, efficacy and potency are not impacted by inadequate sanitation procedures.
There are direct ramifications that come with adulteration and not implementing a cleaning verification and validationprocess? Inadequate cleaning can lead to adulteration of pharmaceutical products through the addition of unintended matter or microbial contamination, such as:
1. Contamination of one batch of product with significant levels of residual active
ingredients from a previous batch
2. Microbiological contamination: Maintenance, cleaning and storage conditions may
provide adventitious microorganisms with the opportunity to proliferate within the
3. Contamination with unintended materials or compounds such as Cleaning agents,
lubricants etc.(Pawar, 2011).
This can result in serious repercussions, including death by those who ingest any 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. Cleaning validation implements a modern risk management plan for a more effective quality control.
The FDA (2011) found the following:
“Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug shall 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".
Therefore, Validation is used to determine procedures and specifications. Verification is used to determine if the specifications determined by validation are met.
Cleaning validation in a pharmaceutical active ingredient area is regulated by the FDA in a pharmaceutical production area, and the objectives of equipment cleaningshall 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 ensures there is no contamination from the equipment and containers. Validation provides a high degree of assurance in the quality of the performance of the cleaning process. In their December 2008 regulatory guidance, the Health Sciences Authority stated that, “Cleaning procedures shall strictly follow carefully established and validated methods of execution(Ion Labs Warning Letter, 2009). 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 prevented.”
The first thing a drug company shall do is pay attention to the objectives of the validation procedures. Of those pharmaceutical companies citedin warning letters, it is not unusual to 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(FDA, 1993). Cleaning validation is essential in securing an effective cleaning process; therefore, a paying attention to every single detail is essential in this matter. The main reason for clean equipment is to prevent tainting of drug products. It is important to follow FDA regulations in terms of the cleaning process for the following reasons:
- Public Satisfaction and Regulatory Requirement: this will assure safety and purity of the drug products.
- Compliance Perspective: this creates an impurity free product, and is a key element in the process of any product stage of manufacturing process.
- Microbiological Contamination: Improper cleaning and maintenance of equipment will
lead to unintentional microbial growth or contamination.
Validation of Sterilization Process
For purity of sterile drug products, the equipment surface that comes in contact with containers, closures or drug product, shall be sterilized. Similarly, it is very important in sterile processing to verify the procedures used to sanitize or sterilize the equipment. Verification requires planned testing to demonstrate effectiveness of all procedures critical to the accuracy and purity of finished CSPs(pharmacopeia.cn, 2010). Sterilization of equipment shallbe maintained between different batches and formulation of different drug products.
Equipment surfacesare to undergo sterilization or sanitization processes to eliminate the possibility microbial organisms. Thus, according to the FDAit 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”(FDA, 1993).Validation is then set in place to improve processes that assure the FDA that there will be no contaminated product. Compounding personnel are responsible for ensuring that CSPs are accurately identified, measured, diluted, and mixed and are correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed, and distributed(drugfuture.com).
Management must aim to oversee employees and confirm they have followed the processes developed for validation:
Compounding supervisors shall ensure, through either direct measurement or appropriate information sources, those specific CSPs maintain their labeled strength within monograph limits for USP articles or within 10% if not specified, until their BUDs. All CSPs are prepared in a manner that maintains sterility and minimizes the introduction of particulate matter(drugfuture.com).
Methods and Analysis
Cleaning validation is directed by regulatory requirements to make sure that remnants from one drug product will not move on to contaminate the next product (FDA, 2006).An efficient cleaning program starts with a properly designed cleaning process. Achieving and maintaining sterility and overall freedom from contamination of pharmaceutical product is dependent upon the quality, status of the components incorporated, the process utilized, personnel performance, and the environmental conditions under which the process is performed (pharmacopeia.cn, 2010). 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(FDA, 2011).
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(FDA, 2011).
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(FDA, 2011).
Cleaning Validation Requirements
Pharmaceutical companies are required by law, to provide 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 shall 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 reportshall address both cleaning circumstances and shall be evidently clear how each given procedure is to be executed.
Major pharmaceutical companiescan 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 shallmaintain and conclude that deposits have been prevented to an "acceptable level".
Important Cleaning Validation Factors
The pharmaceutical company shallconcentrate on the purpose of cleaning validation. Thus, certain points shall 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?
These are important factors in deciding what type of cleaning validation process is appropriate for determining the way various surfaces and pieces of equipment are cleaned. Each different drug manufactured in one company can require a different cleaning process. For instance, CSP environmental monitoring of air quality which can include keeping a buffer area clean by regularly changing HEPA Filters, cleaning and sanitizing work spaces, and personal cleansing and gowning of trained employees is critical in the maintenance of asepsis, and more (pharmacopeia.cn, 2010).
The pharmaceutical company must enforce the steps that are to be used for effective cleaning and those that can be excluded for the most effective validation process.The company shall then monitor each cleaning process for each surface and piece of equipment. Each surface and piece of equipment will have one process for cleaning; this is contingent on the drugs being manufactured. The process can be different for each surface and piece of equipment. Cleaning validation shall begin with equipment examination, followed by sampling and testing which is well documented and accompanied by a manager approved written report.
- Each individual company needs to perform an equipment examination to determine the type of cleaning processes to implement. Employees shall be trained in individual cleaning processes of surfaces and equipment, and be knowledgeable on reports to be filed along with the cleaning.
- Management shall examine the written report and cleaning validation process to regulate propervalidation. According to the FDA, this includes “checking the flow charts and piping diagrams for the identification of valves and written cleaning procedures”(FDA, 1993).Labels are required on all equipment and hardware in order to know what the equipment is and what cleaning procedure is used. Hardware that is not properly labeled can, as a result, not be cleaned properly voiding the cleaning process.
- Employees shall carefully read labels and instructions during the cleaning process. The cleaning process shallbe followed down to the exact protocol, especially with time sensitive cleaning products that can leave deposits or harmful residue. There shall be documentation providing proof that microbial organisms are not present, and stagnant water has not been left on surfaces. Thus, surfaces and equipment shall be hand or air-dried, stagnant remaining on surfaces or in equipment before cleaning procedures can promote microbial proliferation and render the cleaning process invalid. This can allow bacteria to grow thus contaminating entire batches, resulting in inadequate procedures that cause adulterated product, and may or may not lead to adverse reactions in patients with possible consequences to the consumer’s health.
Cleaning Validation Written Reports
Management must inspect all surfaces and equipment. Each process shall require specific documentation as to the amount of paperwork to be kept in specified logbooks. For instance, pharmaceutical company regulations require batch records. In addition to batch records, master records and Material Safety Data Sheetsthat entail each step in the cleaning process shall be filed and approved by management. The length of paperwork will vary depending on the length and strictness of the cleaning process itself. More Intricate cleaning processes will entail critical documentation, especially when cleaning machines that bulk process. Thus, the written reports shall include the name of the employee who cleaned the equipment and also write down the time of their shift.
In regards to cleaning 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 are designed to maintain quality assurance:
A written quality assurance procedure includes the following in-process checks that are applied, as appropriate, to specific CSPs: accuracy and precision of measuring and weighing; the requirement for sterility; methods of sterilization and purification; safe limits and ranges for strength of ingredients, bacterial endotoxins, and particulate matter; pH; labeling accuracy and completeness; BUD assignment; and packaging and storage requirements(drugfuture.com).
Methods of Evaluation for Written Reports
Often residues and contaminants like pyrogens and microorganisms can remain on equipment after a batch is manufactured. Written reports can help monitor the levels of adulterants found on equipment, and help maintain 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 contaminantsgoing un-detected. Not to say there is no deposit whatsoever after a cleaning process. There are indeed acceptable levels on non-contaminants that can be present in various batches of drugs.However, there are un-acceptable levels that can contaminate batches even after a cleaning process. Various analytical methods must 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 surface of the equipment used during processing.
The FDA accepts two types of sampling: one being swab sampling, and the other being rinse sampling.
- Swab Sampling – Management shall run tests to determine what type of swab material shall be used for effective sampling. Case in point, certain adhesives in testing swabs have been proven to interfere with the analysis and produce false data results during sampling and produce a negative sample. Accurate sampling may identify hard to clean spots. New cleaning procedures can then be established and validated to guarantee adulterants are cleaned off of equipment surfaces.
- Rinse Samples – Rinse samples can be most effective in the evaluation of cleaning machines that cannot be moved or disassembled day to day. This is most beneficial to pharmaceutical companies who mass manufacture batches with large equipment. Unfortunately, some 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 cleaning processes that educate employees on examining equipment to test potential residues, deposits and contaminants. Therefore, the employee is examining the equipment and the water left over from any residue.
Tests are run until an effective, valid cleaning process is proved through data. Employees shall test, take samples, and retest surfaces on equipmentuntil deposit level is maintained as satisfactory under FDA requirements. Retesting and resampling must be done on a reoccurring schedule to document whether the cleaning process remains valid or not; thus, maintaining a safe level of residue will help employees eliminate the presence of deposits that render a cleaning process invalid. This will help management restructure cleaning processes until successful levels are maintained.
Swab samples should be tested for:
1) Product residues in accordance with analytical protocol
2) Cleaning agent residues in accordance with analytical protocol(apic.cefic.org,
Rinse samples should be tested for:
1) Product residues in accordance with analytical protocol
2) Cleaning agent residues in accordance with analytical protocol(apic.cefic.org,
Cleaning Validation Process
Employees shall maintain records of detergents, solvents, soaps and products used in the cleaning process to show levels of possible residues 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 positive sample to be taken. Another problem can arise when cleaning products offer no chemical composition or list of ingredients used to create the product. Therefore, these products are not allowed to be used in a cleaning process. Thus, pharmaceutical companies meet FDA regulations. A validated cleaning process will determine the detergents and solvents to be used.
Recalls can occur as a result of adulteration. Recalls may be conducted on a firm's own initiative, by FDA request, or by FDA order under statutory authority(apic.cefic.org, 1999). Adulteration can be prevented with the implementation of a cleaning process and removal of microbes, pyrogens, and foreign matter through cleaning validation and verification. While cleaning procedures are much more stringent for sterile products, validation helps determine the cleaning procedures. The following recalls are the direct result of non-compliant cleaning and sterilization procedures in various pharmaceutical companies:
Hospira Recall: According to the FDA warning letter issued to Hospira Inc., “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)](Teva Warning Letter 2009). For example, 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 informationadulteration lead to product recalls because of an invalid cleaning process.
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) 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 4 minutes. This requirement is described in the procedure entitled (b)(4). The firm has committed to record, the start and stop contact times for the sanitizing solutions in equipment cleaning logs. We will evaluate the implementation of this corrective action during a future inspection, and
b) There is no record to document that the "stock pot" is periodically cleaned and sanitized before use. This "stockpot" is used to manually transfer bulk solution from the bottom of the mixing jacketed vessel to the top of the tank following the process.”Teva voluntarily recalled some of the lots of these emulsions due to lack of sterility assurance. The warning letter tells us that there was no way to prove sterility.
Knoll Pharmaceutical Warning Letter: In the event of non-compliance, the FDA states in the warning letter that they maintain the right to file an injunction againsta pharmaceutical company. They also threaten to perform a seizure of the pharmaceuticals and deny export approval requests for new drug applications. 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”. The drug 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.
The evidence above shows the lack of cleaning validation, verification and inadequate cleaning practices and procedureshas led to significant problems. In nearly 35 percent of cases, a lack of validation procedure was observed. Other validation related observations include a) 11 of 55 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.
Discussion and Conclusions
While it is important to meet specifications and requirements, companies are violating simple cleaning and validation procedures. Ensuring proper training is a valuable mechanism to ensure cleaning processes are correctly followed. Employees must regard cleaning validation as something that is mandatorily in place to ensure their product is safe and effective. Management must be proactive in placing a proper cleaning process into action, and making sure all employees are properly trained. Employees must be diligentin their attention to cleaning processes.
Training is necessary to satisfy quality control systems and good manufacturing practices:
Personnel who prepare CSPs shall be trained conscientiously and skillfully by expert personnel and through audio–video instructional sources and professional publications in the theoretical principles and practical skills of aseptic manipulations and in achieving and maintaining satisfactory environmental conditions before they begin to prepare CSPs. Compounding personnel shall perform didactic review and pass written and media-fill testing of aseptic manipulative skills initially, at least annually thereafter for low- and medium-risk level compounding, and semiannually for high-risk level compounding. Compounding personnel who fail written tests or whose media-fill test vials result in gross microbial colonization shall be immediately re-instructed and re-evaluated by expert compounding personnel to ensure correction of all aseptic practice deficiencies(drugfuture.com).
Equipment inspection procedures must change when there are violations found by the FDA. Individual companies must perform regular examination of equipment with revalidation processes. When evaluating the new cleaning process, the company must add aides in the cleaning difficult areas, like cracks and crevices of equipment. For instance, better lighting can help employees in seeing where to clean. Hand-held mirrors can assist in seeing adulterations in hard to reach cracks and crevices. Some companies even add a hand-wiping test using a white glove. Training for all employees shall then be conducted with classes and ‘on-sight’ educational courses that take them straight to the equipment for visual inspections.
Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level(apic.cefic.org, 2000). Validation is, then crucial in verification. There are a plethora of thingsthat can have impacton the potential for the adulteration of drugs. Thus, effective cleaning processes are a great challenge to drug manufacturers.
Products must also be revalidated in order to determine the validity of control each company has on their products. Scheduled verification procedures are used to ensure the cleaning process is controlled. Additionally, each company must inspect the cleaning process to be aware of any serious considerations. For instance, equipment design must be evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and the cleaning techniques. Also the ruggedness and reproducibility of the cleaning method should be covered(apic.cefic.org, 1999). According to the Active Pharmecuetical Ingredients Committee (1999), “Three consecutive successful samples must be taken in order to validate a cleaning process.” Nevertheless, this is the reason each pharmaceutical company needs to take each situation in on individual level.
Also, there are a set of requirements that each company must have in place that require cleaning to be performed. Cleaning should begin as soon as production has ended, and this alone must be validated. Companies often group batches of products for cleaning, because immediate cleaning is not possible. This is why there is a maximum time in which a piece of equipment can be left dirty before it is used for processing again. Companies must have SOPs in place to ensure that pieces of equipment are adequately protected from any contamination after cleaning has taken place: i.e. ensure that the equipment is adequately covered, closed from dust, etc(apic.cefic.org, 1999).
Companies often perform verification procedures after cleaning validation in order to monitor data rendered in this process. Validation and verification are both appropriate for routine manufacture of pharmaceuticals. A validation and verification are both essential where there may be a potential for contamination. It is important that the requirements for the finished manufacturing companies are not transferred back in the process to active pharmaceutical ingredient manufacturers without consideration for the different processes that take place during validation (apic.cefic.org, 1999).
In the end, the test of any validation process is to show whether scientific data proves that the system produces a result that consistently meets predetermined specifications(Pawar, 2011). The goal of cleaning validation is reached, and the quality, safety, efficacy and potency are not