Steam Sterilizer Validation Requirements Per The New Standard ISO 17665-1:2006

For decades, steam sterilization (autoclaving) has been an integral part in the manufacturing, cleanroom, and laboratory processes for the medical device, pharmaceutical, biologics, and human tissue/HCTP industries. It has been a common industry practice to validate steam sterilizers using the published guideline ISO 11134 Sterilization of health care products — Requirements for validation and routine control - Industrial moist heat sterilization,¹ issued in 1994. In late 2006, AAMI released the document intended to supersede 11134, with ANSI/AAMI/ISO 17665-1:2006 Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.² While other steam sterilizer guidance documents do exist,^3,4 it is anticipated that the new 17665 standard will be recognized by the FDA and will be commonly employed to validate autoclave processes. The good news to manufacturers or other users of these guidelines is that many of the current validation practices are the same in the new document. This article will outline the basic requirements for steam sterilizer validation via the halfcycle overkill method, and list some of the differences between the two documents.

REQUIREMENTS PRIOR TO VALIDATION
The 17665 document makes it clear in numerous locations that the user’s quality system must adhere to ISO 13485:2003 Medical devices — Quality management system — Requirements for regulatory purposes.⁵ So if a user wishes to claim full compliance with the new 17665 steam standard, then their quality system must also be in compliance with ISO 13485, including items such as preventive/periodic maintenance and regular calibration for the sterilizer, documentation, change control, purchasing, etc. When compared with the previous steam document, the new 17665 also has more information on product and process characterization, sterilizing agent characterization, installation qualification/IQ, and operational qualification/OQ. The new document also states more clearly that a fully compliant validation is not just a series of successful halfcycles,but is the full complement of successful IQ, OQ, and PQ.
Sterilization agent characterization will be simple for most users — moist heat/steam at 121 or 132 °C, and cycle selection (gravity, prevacuum, etc.). Process and equipment characterization means defining and documenting items like the sterilizer cycle parameters, products (or product families) to be sterilized, load configurations and limits, placement of biological indicators or chemical indicators (BIs/CIs), process tolerances, and equipment identification. Much of this type of information would be recorded in well-written validation protocols or validation final reports. Biological indicators often use spores of the bacterial species Geobacillus stearothermophilus at a titer of greater than 106per BI, although other species or titers are sometimes used.
The new 17665 document also has more information on IQ and OQ. It defines IQ as “obtaining and documenting evidence that equipment has been provided and installed in accordance with its specification.” Autoclave installations commonly document items such as the sterilizer identification numbers, location, line voltage and amperage, water supply piping and pressure limits, steam line requirements, filtration, chamber size, structure and support, piping materials, software certification, manuals, drawings and documentation, and calibrations (temperature, pressure, and timer). The sterilizer must be installed in such a manner to facilitate any necessary maintenance, repair, adjustment, cleaning,and calibration.
OQ is defined as “obtaining and documenting evidence that the installed equipment operates within predetermined limits when used in accordance with its operational procedures.” Autoclave OQs commonly test or verify items such as cycle operation and programming instructions, safety and alarm testing,error reporting, empty chamber temperature profiling and chamber temperature limits/specifications, air removal testing, leak testing, temperature control anomalies, full cycle full-load temperature profiles (if proposed fullcycle exposure time is known), and determination of any hot or cold spots withinthe chamber.
The product definition and process definition sections of the new document list things such as product specifications, product families, packaging, re-sterilizationissues, package moisture, stability and potency of container products, re-usablecontainer systems, process challenge devices/PCDs, sterility assurance level/SAL,BIs and CIs, and bioburden determination if necessary. PCDs are described asproducts or items that provide a known resistance to the sterilization process.They are commercially available or may also be created from the user’sproduct line by inserting spore strips, spore dots, inoculated threads, etc.into items or locations that are determined to be the most-difficult-to-sterilizeproduct or location in the load.
There are many other activities or decisions to be made prior to or during the IQ/OQ, that are not necessarily detailed in either standard. Items such as:

• Obtaining calibrated temperature recording devices or thermocouples
• Ordering supplies such as BIs, CIs, Bowie-Dick test packs, packaging materials, etc. and noting if adequate laboratory facilities are available
• Determining worst-case validation load and worst-case test product or PCD. The protocol or final report should contain a written rationale describing how the loads and product(s) were selected
• Selecting cycle type: 121 or 132 °C, gravity or prevacuum cycle, etc.; and determining if drying time needs to be qualified
• Is product bioburden testing necessary?
• Is product resterilization to be allowed and what are the requirements for resterilization?
• Is product stability or shelf life testing necessary for the user’s products?
• Does packaging testing or packaging validation need to be included with the protocol?

VALIDATION – PERFORMANCE QUALIFICATION
AAMI TIR #13 states “Sterilization process validation is a documented procedure for obtaining, recording, and interpreting the results required to establish that a process will consistently yield product complying with its predetermined specifications.” For the purposes of this article, the primary specification will be sterility. The performance qualification/PQ or microbiological qualification is a series of tests that establishes that the installed and properly operating sterilizer will process the users desired chamber loads to achieve the specified sterility assurance level/SAL. It must be remembered that the load is part of the validation — that is, if the user makes significant changes to the load at any point in the future — then re-validation may be necessary. The previous ISO 11134 document gave relatively little guidance information and few specifications for conducting the test cycles necessary to qualify the user’s proposed fullcycle exposure time(s). The new 17665 steam document varies little from the previous standard in respect to the minimal PQ information that is provided. The 17665 describes bioburden validation methods and the more commonly used halfcycle “overkill” method. It should be noted that at the time this article was prepared, the proposed guidance document that is to accompany ISO 17665-1 was not yet available. This guidance document may provide more advice on microbiological qualification issues (ISO 17665-2 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1). For this article, the general requirements for an overkill cycle PQ will be reviewed.
While many activities are required to complete the PQ, the primary goal for the commonly employed overkill validation is this: the user needs to complete three consecutive successful halfcycles in order to qualify their proposed fullcycle exposure for routine processing of sterilization loads. In our case, successful means all BIs are killed (no growth upon incubation) for the three consecutive halfcycles. If, for example, there was no BI growth for the three test cycles at ten minutes exposure at 121 °C, then a 20-minute exposure at the same temperature would be adequate for routine daily processing, assuming all other aspects or requirements of the IQ/OQ/PQ are successful, documented, reviewed, and approved.
But a description of the PQ needs much more detail than this. Validation protocols vary in format from company to company, but most will capture similar information for the final report. An example of validation protocol and final report sections would be:

• Title page with approval signatures
• Purpose, background information, or general goal(s) of validation
• Scope with more specifics about methods, cycles, facility, SAL, products and load, exclusions, etc.
• References with published standards and company SOPs
• Equipment, supplies, validation loads, BIs, etc.
• Rationale for selection of products, load, cycles, PCDs, etc.
• Procedure or methods (more details on this below)
• Acceptance criteria which list the pass/fail requirements
• Deviation report which lists any unexpected results, with potential effects on the validation, along with accept/reject rationale
• Results and conclusions which assign a pass/fail decision to each acceptance criteria, summarize study, and include any requirements for revalidation
• Attachment which lists any data sheets, diagrams, certificates, temperature records, etc., for inclusion with final report
• Approvals section for final report.

To conduct the halfcycles, the user assembles the worst-case validation test load, temperature loggers, BIs/PCDs, and CIs if necessary. The temperature loggers and BIs are seeded throughout the load to represent various chamber locations, keeping in mind any cold spots or previously determined most-difficult-to-sterilize locations. For small chambers, as few as five or six BIs and temperature loggers may be needed. Ten is a common sample size for many chambers. Large, multi-pallet-sized chambers may require many more samples per run. The sterilizer is programmed for one-half of the proposed full-cycle exposure time. Upon completion of the test cycle, the BIs are immediately removed and incubated, and the test load must be allowed to return to normal temperature prior to starting another test cycle. Temperature recorder data is downloaded and printed immediately to determine if any unusual temperature conditions existed. Information is entered on thedata sheets (data sheets that would have been one of the attachments to the written protocol), and all temperature records and data sheets are retained for the final report. BIs are checked regularly throughout the incubation period, and include positive control (unprocessed) BIs which must show growth. As stated before, all processed BIs must show no growth in order for the validation runsto be considered successful.
Final reports should contain: 1) all sterilizer run data or recorder charts, signed and reviewed; 2) all temperature recorder data, signed and reviewed; 3)all data sheets with BI, CI, or any other test results, reviewed and signed;4) any deviations recorded and investigated, with final disposition; 5) results,conclusions, and discussion; 6) calibration documents for any measuring instrumentsused during the study; 7) the approved full-cycle parameters and acceptable placementlocations for BIs for normal processing; and 8) manufacturers’ certificatesof analysis for any items such as BIs, growth media, growth promotion test cultures,etc. Including digital photographs of sterilizer, load, PCD, etc. can be quitehelpful for an auditor who may be reviewing the report at a later date. The completedfinal report packet must then be routed for review and signed for approval.
POST-VALIDATION
There are still issues to be addressed when all activities seem to have been completed. The sterilizer must be added to a regular and documented calibration program. The sterilizer must be included in a regular and documented periodic/preventive maintenance program. And the sterilizer must be added to the validation schedule for its annual requalification. The user needs to verify that all personnel that will be using the autoclave are trained using applicable operation and safety SOPs. Untrained staff should not be allowed to run the sterilizer. Approved products, loads, cycles, and load limit information must be readilyavailable to all operators. SOPs for daily processing must list all requirements for data that is to be reviewed and retained from the sterilizer runs, with logbook, filing system, or archive for run records. SOPs must also address items such as 1) segregation of processed and non-processed product, 2) storage requirements for processed products if necessary, 3) notification of management or maintenance if sterilizer malfunctions or if recorder chart lists any errors, cautions, or warnings, 4) immediate notification of management for BI test failure, including investigation and product quarantine procedure as appropriate, and 5) resterilization requirements if resteril-ization isto be allowed.
In summary, there seem to be no drastic or revolutionary changes in making the transition from ISO 11134 to ISO 17665. The new 17665 steam document provides more information and more guidance in some areas, while leaving other areas (such as PQ) relatively unchanged. While users would be advised to obtain the 17665-2 guidance document when it becomes available, it is anticipated that manufacturers will not find any great difficulties in applying the new standard.
References

1. ISO 11134:1994. Sterilization of health care products — Requirements for validation and routine control — Industrial moist heat sterilization.
2. ANSI/AAMI/ISO 17665-1:2006. Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.
3. AAMI TIR No. 13-1997. Principles of Industrial Moist Heat Sterilization.
4. PDA Technical Report #1. Validation of Steam Sterilization Cycles. Parenteral Drug Association.
5. ISO 13485:2003. Medical devices — Quality management systems — Requirements for regulatory purposes.

Evaluation of Validation Content Uniformity Test Results Using Lower Probability Bound Distribution Charts

By Pramote Cholayudth

 

 

One of the widely recognized references on process validation with regard to sampling and testing plans is the US Food and Drug Administration’s Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment (1) that is based on the Product Quality Research Institute (PQRI)’s Recommendation Report (2). However, it is a non-binding document (i.e., the industry may use any alternative approaches even after it becomes the official guidance). Another well-known relevant reference is the PDA Technical Report No. 25: Blend Uniformity Analysis: Validation and In-Process Testing (3). The sampling, testing, and corresponding acceptance criteria limits in validation study will follow these two statistics-based documents. The validation test results with respect to critical quality attributes (CQAs) require to be statistically evaluated (e.g., estimating confidence limits as appropriate, demonstrating the high probability of passing the tests, etc.).

   

According to Torbeck (4), “… If statistical procedures were given in the USP, companies would have little incentive to develop better procedures.” His comment is now reconfirmed. The industry may not have a good approach like J.S. Bergum’s method if the United States Pharmacopeia (USP) provided some kind of statistical procedures. Bergum is one of the leading professionals who suggested the use of the new statistical procedures. His methods (5, 6) introduced both how to establish the validation acceptance criteria and how to evaluate the validation test results. In protocol development, all the validation practitioners may follow some recognized documents including Bergum’s in establishing the acceptance criteria limits. However some of them may not be confident in using statistical tools for evaluation of the test results, especially for the multiple stage tests (e.g., content uniformity and dissolution).

   

To provide an alternative to such a statistical evaluation, this article introduces an approach to using lower probability bound distribution charts, constructed according to Bergum’s methods, for evaluation of content uniformity test results.

Laboratory Equipment Validation and the Importance of a Manufacturer

Many types of equipment in both manufacturing and laboratory areas are critical to a properly functioning pharmaceutical process. The validation of laboratory equipment is not as clearly defined as the validation of equipment used directly in the production of pharmaceutical products, which requires thorough validation in almost all situations.Should My Laboratory Equipment Be Validated? The evaluation should begin by determining the requirements of the end user, which are often defined in the User Requirements Specifications (URS). Additionally, it is critical to consider the laboratory applications as well as the associated equipment. Next, a risk analysis should be performed. Some types of equipment may seem less critical, but upon more thorough analysis, their real importance is revealed.
Responsibility for complying with the appropriate industry standards ultimately falls on individual companies, divisions, or departments. Failure to comply with current good manufacturing practices (cGMPs) or good laboratory practices (GLPs) can have serious consequences, including regulatory restrictions — such as the inability to sell the product.

Validation reduces the risks of non-compliance with regulatory agencies. It also can reduce compulsory in-process controls and testing. Validation is a means of improving procedures and final product quality. Rather than adding constraints imposed by regulatory bodies, validation is a process for improving efficiency and quality that ultimately can lead to cost savings. Pharmaceutical companies are responsible for the qualification and validation of their equipment. As a result, they must be able to justify choices concerning these procedures to a regulatory agency auditor. The documented evidence supporting these choices is one of the fundamental requirements of validation. After all, validation is verifying and documenting with a high degree of assurance that specific equipment will perform consistently according to predetermined specifications. The documented evidence presented also must comply with cGMPs, incorporate preventive maintenance, and include a requalification schedule.
It is important that the pharmaceutical company works in conjunction with equipment suppliers to determine the appropriate validation protocols as well as the frequency of requalification. A manufacturer's validation capabilities can be an indicator of the quality of the equipment being supplied.

Water Purification Systems To further discuss validation principles, a single system with downstream effects on manufacturing and testing processes will be examined. The data in a laboratory is impacted by a variety of instruments, including water purification systems. If the water system does not consistently produce purified water, the validity of the data from these instruments can be compromised. Manufacturers' Capabilities When acquiring equipment, particular attention must be paid to the equipment suppliers' ability to provide either direct or indirect help with equipment validation and qualification — even if the qualification will be performed by internal qualification services. When choosing a water purification system that will be validated, it is important to consider more than just the specifications of the water produced. Other equally important factors should be considered, such as the level of service provided and the manufacturers' validation experience. In order to meet user requirement specifications and regulatory guidelines, an equipment manufacturer that has implemented a comprehensive program must be chosen to ensure that their products can be qualified. Evaluation should include consideration of the manufacturer's design, manufacturing process, quality controls, traceability, documented evidence, training for users and service personnel, support for periodic maintenance, qualification, requalification, and other factors (see Table 1).
Water purification systems are essential pieces of equipment in most pharmaceutical laboratories for drug production, drug testing, and quality control applications. The quality of purified water used in these processes ultimately can affect the quality of the final product. This is why organizations such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) frequently state that water purification systems must be validated. As with any other equipment, it is important to work with the water purification system manufacturer to determine the appropriate qualification protocols, how to carry them out, and an appropriate requalification schedule. The manufacturer's knowledge can be crucial, especially if they have developed specific documentation to assist with validation procedures. In addition to meeting cGMP requirements, this documentation also should be applied to each qualification stage and offer users comprehensive help in conducting system qualification.
The engineers who deploy system qualification protocols should be trained in validation procedures and familiar with production processes and regulatory requirements in the pharmaceutical industry. Furthermore, preventive maintenance helps ensure that the water purification system is kept in optimal condition and prevents down-time.
Validation Parameters Since the system qualification begins at the design stage, it is important to have a qualification team involved in the development of all new systems. This enables the manufacturer to incorporate the pharmaceutical requirements for system design and specifications.
An important parameter to be considered for the qualification of water purification systems is the calibration of measuring instrumentation. The product water should be monitored continuously for conductivity and, if required, total organic carbon (TOC) levels using calibrated instrumentation. Water purification systems should be designed specifically to meet USP 28 <643> and <645> suitability test requirements for TOC and conductivity respectively. Also, as recommended by FDA, system alerts should be implemented to warn users if the system is performing outside the pre-determined specifications. Additionally, systems manufactured in an ISO 9001/ISO 14001 certified plant permit good traceability. Certificates of Conformity, Certificates of Quality, and Certificates of Calibration also should be available. The USP specifies that operational qualification protocols be performed on-site after the system has been installed to meet USP validation requirements.
Conclusion Equipment validation is essential. Determining what equipment needs validating starts with ascertaining the requirements of the end user. It then proceeds to a risk analysis with careful attention paid to regulatory requirements. Careful choice of an equipment manufacturer that offers a comprehensive validation services program, incorporating specially-trained personnel, on-site qualification protocols, calibrated measuring instrumentation, and the relevant documentation in accordance with GMP requirements can facilitate the validation process and overall regulatory compliance.
Sean Murphy is worldwide validation product manager for the Lab Water Division of Millipore Corporation, Boîte Postale 307, 78054 St. Quentin en Yvelines Cedex, France, (33)1.3012.7232, sean_murphy@millipore.com

Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility

Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility

Understanding every aspect of the process should ensure development of a successful cleaning validation program.

Feb 1, 2006 By: José A. Morales Sánchez

José A. Morales Sánchez

Currently, there are multiple publications, as well as guidelines from regulatory agencies that make the critical process of equipment cleaning validation easier. These sources provide in-depth information for the validation specialist, making the development and implementation of a robust cleaning validation program possible within any particular facility developing or manufacturing parenteral, biological, or sterile ophthalmic products. Extremely important, specific, and above all, mandatory, are the requirements established by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration (TGA), etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states:
"Equipment and utensils shall be cleaned, maintained, and sanitized 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."
Additionally, Section 211.182 requires that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established.
This article provides the reader with cleaning validation information enhanced by the author's thirteen years of hands-on experience working in equipment cleaning validation. SCOPE
This article focuses on manual cleaning procedures because these are considered the worst-case scenario. It applies to parenterals, ophthalmic, and biologic presentations and is intended to cover equipment validation for raw materials, contaminants, cleaning agents, as well as the control of potential microbial contaminants associated with those products.

Figure 1. Depiction of Different Aspects for Consideration When Developing a Cleaning Validation Program

The flowchart in Figure 1 graphically shows the different aspects that should be considered when developing a cleaning validation program. Understanding each aspect of the process, the relationships among these actions, and the sequence in which they should take place will make the development of a cleaning validation program a successful experience. PROCESS FLOW
After all applicable cleaning information sources and regulatory guidelines have been consulted, the first item to consider when establishing a cleaning validation program is the raw material and final product flow. By following the flow of the product, one can identify the equipment that comes in contact with it, such as utensils (scoops, spatulas, funnels, pipettes, etc.), tanks, filter housings, pressure vessels, syringes, and others. Equipment such as this is considered critical equipment because it comes in direct contact with the product.
Other areas where raw materials or products are processed, which might be considered non-critical because they are not in direct contact with the product, should also be considered. From the point of view of microbial load, inappropriate cleaning and sanitation of these areas may contribute to cross-contamination. Some examples of these areas include: sampling and weighing rooms, as well as formulation and filling rooms.
Typical steps to follow in process flow are as follows:
Raw Materials Sampling: Raw materials include both active and inactive ingredients. Many active ingredients are potent compounds, such as steroids, cortisone, antibiotics, proteins, and therefore it is important to demonstrate their removal. But be aware that some inactive ingredients have poor solubility in water and their residues may be more difficult to remove than those of an active drug.
Utensils used during the sampling process of raw materials require cleaning validation unless they are disposable. Typically, use of disposable utensils is the preferred practice for parenteral and biological products. The sampling of raw materials should be performed within a controlled environment (classified as 1,000, 10,000, 100,000, etc.,) in order to reduce the introduction of non-intrinsic contamination to the process. Some firms use extraction hoods equipped with high efficiency particulate air (HEPA) filters and room air conditions that provide an acceptable environment for raw materials sampling. In addition, sampling area and rooms should be cleaned with sanitizing agents. Cleaning effectiveness on those surfaces should be challenged using microbiological tests for verification of bioburden reduction of non-sterilized parts, such as tables, walls, ceiling, fillers, etc.
Weighing of Raw Materials: Some rules followed during raw materials sampling also apply to the raw materials weighing process. Some ingredients will require being weighed inside a glove box due to special environmental requirements (e.g., under nitrogen, etc.). Because glove boxes are usually shared, they too will require cleaning validation.
Product Compounding: This is one of the most critical steps because the equipment used will have direct impact on the finished product. Compounding a finished product requires equipment with large product contact surface areas. The handling of ingredients requires utensils with less product contact surface area. This significant difference is important because the more complex the equipment, the more samples must be taken to demonstrate effective cleaning.
Product formulations involve the use of tanks and ancillary equipment, such as gaskets, pipes, hoses, mixers, and filter housings. Gaskets and hoses are disposable in many pharmaceutical processes, so they do not generally require cleaning validation.
Product Filling: Filling of parenteral, ophthalmic, and biologic products is usually performed within areas of controlled bioburden, ranging in scale from clean to aseptic rooms. Drug products are capable of being contaminated in many ways. Contamination may occur via filling components (tips, caps, bottles, or stoppers); when coming in contact with processing equipment (tanks, manifolds, fillers, machine-syringes, pistons, and blocks); the manufacturing environment, or manufacturing operators.
Some equipment may require cleaning revalidation if components come in contact with the product. Stoppers are siliconized and then are placed in a hopper during filling. Small quantities of silicone are accumulated in the lower part of the hopper where it can degrade over time. If this silicone were to come in contact with the product, it would probably cause product contamination.
Requirements for aseptic processing include cleanable floors, walls, ceilings, particulate, temperature, humidity, cleaning, and disinfecting procedures. When disinfectants are used in the manufacturing area, care must be taken to prevent the product from becoming contaminated with chemical disinfectants. The selection of suitable disinfectants, verification of their effectiveness, and a surface challenge are critical in developing a cleaning and sanitization program. Written procedures for cleaning, maintenance, and sanitization of manufacturing equipment and appropriate areas of the facility are required. Removal of residual disinfectants should be monitored as a precaution against the possibility of product contamination.
Know Product Ingredients and Intended Use of the Final Product
Previous to designing the cleaning procedures, it is necessary to know all physical and chemical characteristics of the product ingredients. Characteristics such as appearance, solubility, potency, and toxicity play an important part in the design strategy of a cleaning validation program. These characteristics will indicate whether solvents or detergents are needed for removal of product residues. Avoid the use of detergents or solvents whenever possible because their use demands added controls.
Regarding the intended use of the product, cleaning procedures related to the production of parenterals are the most critical. Great precautions should be taken with the cleaning procedures surrounding these products, because they will be intravenously administrated to patients and any adverse reaction could cause serious damage to patient health.
Developing Standard Operating Procedures (SOPs) for Cleaning Processes
Once we know and understand the product process flow, the product's ingredients, and the product's intended use, standard operating procedures associated with the cleaning process should be established. These procedures should clearly address the specific method chosen, the cleaning process itself, any detergents, and the allotted cleaning time.
There are three types of cleaning procedures for process equipment: automated Clean in Place (CIP), Clean out of Place (COP), and the manual process. However, the major concern of regulatory agencies has targeted pieces of equipment that will be cleaned manually, and where the primary responsibility for the removal of product residues lies with the cleaning operator. In the case of manual cleaning methods, the effectiveness of cleaning depends upon the design of the procedure and the commitment of the operators to follow that procedure. This requires a well-explained SOP, personnel training, and operator commitment. With all three elements present, reproducibility of the results in terms of removal of product residues from equipment surfaces can be achieved.
Cleaning procedures should cover every type of equipment to be cleaned. They should specify all critical parameters including water flow, temperature, and pressure as well as washing and rinsing times. Usually these will have been previously set through engineering studies. Cleaning procedures should also include specific details regarding disassembly of equipment, where the small parts should be placed, the quantity of detergent to be prepared and its concentration, and the type of brush or piece of cloth used to apply the detergent. The size (length, and internal diameter) and the type of hose used to perform the cleaning process should also be specified. This is important because, if the hose diameter is small, less water is used and a higher pressure is achieved during the operation. Finally, cleaning procedures should be challenged and validated to demonstrate the reproducibility of results for all cleaned parts.
Validated Analytical Methods
Appropriate validated analytical methods for analyzing cleaning validation samples will be used. A validated method is rugged and robust enough to measure the residue limit established. The method used should be based upon previously established residue limits of the active, cleaning agents, and excipients. The method must be appropriate for measuring the analyte at and below the acceptance limit for residue.
Two important parameters in an analytical method used for cleaning validation are: the Limit of Detection (LOD) and the Limit of Quantitation (LOQ). The LOD is the lowest amount of a compound that can be detected. The LOQ is the lowest amount of a compound that can be quantified. The LOD is usually lower than the LOQ, but is never higher. The LOD should never be used to establish residue acceptance limits. Residue acceptance limit should be established based on LOQ for accurate measurement.
One of the important considerations in choosing an analytical method is the type of residue to be analyzed. Residues can be active drugs, cleaning agents, or organic compounds. The methodologies available are either specific or nonspecific. A specific methodology detects a unique compound in the presence of potential contaminants. Some examples of specific methods are high performance liquid chromatography (HPLC), ion chromatography, atomic absorption, capillary electrophoresis, and other chromatographic methods. Nonspecific methods detect any compound that produces a certain response. Some examples of nonspecific methods include total organic carbon (TOC), titrations, pH, and conductivity. Currently, methods that are complimentary to each other are applied to cleaning validation samples. That is, if a specific method is used for active and cleaning agents, then a nonspecific method, such as TOC can be used as a complementary methodology. Cleaning validation methodology includes other important parameters such as linearity, ruggedness, method precision, and reproducibility.
A method used to analyze cleaning validation samples is properly designed if it identifies possible interferences. Many possible sources of interferences include active drugs and excipients, cleaning agents and compounds, swab materials, and solvents used in performing the cleaning process. Still other sources of interference may be triggered when a sample is not handled properly.
In addition, the method validation must contain sample stability for the reference analyte. Choice of validation methods should guarantee that samples remain stable for the time specified for analysis. This includes the stability of all residues that specifically determine the active and the detergent residues.
Validated Swab Recovery Study
The swab recovery must be validated to determine the amount of analyte that can be recovered from a surface. Previous to validating the equipment cleaning procedure, the types of equipment surfaces for product manufacturing should be identified. This means if four types of surfaces are identified such as glass, stainless steel, Teflon, or rubber; each of the four surfaces must be tested for swab recovery.
The study can be performed on simulated product contact surfaces. The efficiency of the swabbing procedure should be challenged at the acceptance criteria level for active ingredient, excipients, and detergent.
Known amounts of active ingredient, excipients, and detergent will be added to each type of surface. The surface is air-dried and swabbed. The nature of the swab extraction is dictated by the analytical method, which has taken into consideration its dissolution properties as well as the analytical technique used. The amount recovered by the swab is determined using a validated trace level analytical method.
Recovery from the surface is calculated as follows: A recovery factor of 70% is usually acceptable; but factors as low 50% may be obtained. In cases where low results are obtained in a reproducible manner, the sample surface area may be sampled again using a second swab,with the results obtained from both swabs added together.
Initial Cleaning of New Equipment
Another important aspect to consider when establishing a cleaning validation program is the initial cleaning of new equipment. Most commonly, the equipment included in a cleaning validation study is that which currently is in use for a specific operation. Nevertheless, it could happen that new equipment purchased for any type of improvement or replacement is received and installed at the site while the equipment validation study is being developed. In such case, this is the best time to include the new equipment in the study.
Initial cleaning for new equipment requires some special considerations as noted here. This cleaning should be performed to eliminate foreign matter or residues introduced through maintenance, fabrication, or installation.
Description of this initial cleaning procedure is as follows:

• Equipment should be passivated (if stainless steel material) as per current SOP.
• Remove passivation residues from equipment surfaces as per existing cleaning SOP.
• No detergent will be used during the cleaning process.
• Let equipment dry, rub a lint free piece of cloth (preferably white) over equipment surface and inspect the piece of cloth for visible residues.
• Take rinse or swab samples to determine the absence of passivation agents by a validated methodology. Additional samples can be taken for pH/conductivity or any organic reagent determination by TOC technique. In some cases, a sample for total plate count determination is also included.
• The rinse sample for passivation agents will be collected in a 500 mL glass bottle and the sample for organic test by TOC determination, in a 50 mL glass tube.
• The microbiological samples will be collected in sterilized sampling bottles. When swabbing is called for, a sterilized swab should be used.
• Take samples as controls from the water source for chemical tests, TOC analysis, and micro-biological analysis, respectively.
• Submit the samples to the corresponding laboratories and analyze as per current SOP's.
• Acceptable limits:

• Passivation agents: ID test according to the chemical used in the passivation process
• TOC: Three log reduction of passivation agent's formulation or USP limits
• Conductivity: USP limits
• Total Plate Counts: The most important consideration in setting any limit here is that it have a scientific basis supported by historical data.

CLEANING VALIDATION PROTOCOL
Once all the aforementioned aspects are considered, we are ready to develop the cleaning protocol. A protocol used to validate the cleaning procedure contains the following basic elements:
A. Purpose: This section describes the intention of the validation protocol.
B. Scope: This lists the boundaries of the project to be validated.
C. Responsibilities: Tasks are listed for each person involved in executing the protocol.
D. Strategy: The following steps should be included in the strategy section:
1. Description of the product to be challenged:

• If two or more product presentations are used, the more concentrated should be challenged.
• Bracketing may be considered acceptable for similar products and equipment, provided appropriate scientific justification is present.

2. Holding time period for equipment being cleaned:

• This is the time during which the equipment was soiled with the product.
• Let the residue dry for a specified length of time (hours), followed by cleaning the equipment.

3. Holding time for cleaned equipment:

• The rationale to establish this period of time should be based on microbiological challenges in equipment areas identified as inaccessible locations or where the probability of stagnant water can exist.

4. References
5. Cleaning effectiveness measures (rinse or swab)
Measuring and Test Equipment
Check calibrations of instruments used during protocol execution for proper compliance.
Procedure
1. Identify the procedure to be challenged.
2. List all safety precautions established for the affected area.
3. Indicate the number of runs that will be made
4. Describe the equipment to be cleaned, including:

• Equipment pictures
• Indicate equipment surface area calculations

5. List chemical tests (active, detergent, excipients, pH, and conductivity, as applicable to the method)
6. Indicate the number of samples to be collected, the volume of rinse (mL), the container (e.g., glass) material, etc.
Selection of Acceptance Criteria
Chemical Limits
For any new product, the owner should be consulted for details concerning the therapeutic potential and possible adverse reactions. A determination should be made as to the appropriateness of the limits for that product. If the product is determined to be highly potent or poses the strong possibility of adverse reaction, special limits must be determined. All special limits should be determined on a case-by-case basis.
The lowest therapeutic dose (LTD) of 1/1000 is considered a safe level for residues of active ingredients. The same approach will be adopted to calculate the contamination limit for the cleaning agent, using LD50 instead of LTD. For the products that have excipients, (e.g., preservatives), the acceptable residual level should be set at not more than 1/1000 (three log reduction) of TOC of the product formulation.
The maximum allowable carryover (MACO) limit for the active drug or cleaning agent in mg per swab for a specific piece of equipment or for an equipment process train is as follows:
MACO (mg/swab) =






Where:
LTD = Lowest therapeutics dose (mg) or LD50 for cleaning agent (mg/kg)
D = Highest maximal daily dose (dose units)
W_b = Smallest batch size (g)
W_t = Highest unit dose weight (g)
S_s = Swab area (cm² or in² )
S_e = Equipment product contact surface area (cm² or in² )
R = Recovery factor of active ingredient or cleaning agent
LD50 = Lethal dose of 50% of animal population
Microbiological Limits

• Depend on the type of product (e.g., injectable, etc.)
• The most important consideration in setting any limit is that there be a scientific and historical basis.

Discrepancies
Collect any unexpected situations that occurred during protocol execution.
Approvals
List approvers will vary with each firm. At the very least, the following should be included: a validation specialist, head management of the affected area, appropriate representatives of the microbiological and chemistry laboratories, and appropriate QA representatives. The protocol must be approved before execution begins.
FINAL REPORT AFTER PROTOCOL EXECUTION
The final report will include the following:
1. Table of Contents
2. Introduction

• Include a brief description of the cleaning process that was validated.

3. Data analysis and results

• Summarize all validation outcome (use of tables is recommended)

4. Deviation

• Any discrepancy found during protocol execution should be satisfactorily explained.

5. Conclusions
6. Approvals

• The same personnel who approved the validation protocol should approve the final report. These individuals included a validation specialist, head management of the affected area, appropriate representatives of the microbiological and chemistry laboratories, and the appropriate QA representatives.

MONITORING SYSTEM
The purpose of monitoring is to assure the adequacy of the equipment cleaning process. It is important to verify that the cleaned equipment performs as it was intended and that it remains in a validated state. Monitoring may be achieved through taking representative samples, and evaluation of product non-conformances; by following through on quality alert notifications and complaints and by conscientiously completing "Annual Products Reviews." Any or all of these should be followed by revisions to change controls as needed.
Failures in any of these areas might indicate the need for revalidation. Revalidation is also required when there is a significant change in product formulation, change, or modification to a process or equipment and change of cleaning agents.
COMMON ERRORS AND RECOMMENDATIONS
The section is based on the author's experience during his 13 years of dealing with cleaning validations.
Common Errors
1. Failing to perform a good process flow, beginning with the raw material sampling process and focusing on obviously important stages such as the compounding or filling process.
2. Failing to train operators well, and failure to instill a sense of high commitment:

• Most common mistakes, such as not following procedures, not taking samples at the time specified, improper handling of samples, not reporting discrepancies observed during the specific process executed, etc., undermine high quality performance and contribute to poor results. It is highly recommended to have representation from the validation department present throughout all runs.

3. Missing or inaccurate documentation:

• In addition, to the common errors noted above in #2, a lack of documentation also causes difficult situations during future audits, because important key information will be missing during investigations. This is often the basis for general misunderstanding of data.

4. Lack of good coordination and communication between the different areas involved in the validation process:

• Examples of poor coordination and communication include samples not being taken on time, required materials not being available, disputes within departments, lack of cooperation, and bad working environments based on placing blame rather than on cooperation.

5. Failing to understand the criticality of the sampling process:

• It is very important to take the samples at the time(s) established and for the proper durations (stability), taking correct quantities and volumes, attending to the proper handling and storage of samples, using the correct equipment, and other special considerations for samples requiring microbiological testing.

6. Failure to properly train persons in charge of sampling:

• This can have a major impact on the accuracy of microbiological sampling.

7. Not having an effective change control program:

• Once the validation process is completed, internal procedures impacted by the validation outcomes must be revised accordingly. It is frequently observed that the communication and follow up systems fail at some point and impacted procedures and activities are not modified.

8. Not having an adequate cleaning monitoring system:

• It is frequently observed that changes are made to an already validated system, disregarding the impact those changes might have on the validation state of the total system. Constant communication between manufacturing and the validation department is critical.

9. Failure of manufacturing areas to consider the validation department in internal changes and procedure approval:

• Due to lack of technical knowledge in the validation area personnel in manufacturing might overlook or be unaware of important aspects that have impact from a validation point of review.

10. Failure of plant personnel primarily focused on the manufacturing operation, to require compliance with the cleaning validation procedures.
José A. Morales Sánchez is a technical services senior scientist at Janssen Ortho LCC a Johnson ' Johnson Company; 787.272.7463;
.
REFERENCES
1. FDA. "Guide to Inspectors of Validation of Cleaning Procedures," 1993.
2. Technical Tip #3020. "Pharmaceutical Product Contact Surface Sampling." Steris Corporation (Calgon Vestal Division), 410-200-3020. 4/97.
3. PDA Pharmaceutical Cleaning Validation Task Force, "Points to Consider for Cleaning Validation," Journal of Pharmaceutical Science and Technology, Technical Report No. 29, Volume 52, Number 6, 1998.
4. Maria J. Capote, "Documentation For Cleaning Validation: A Protocol Template," pgs 261-271, Volume 2-Number 3, Journal of Validation Technology.
5. Gil Bismuth and Shosh Neumann, "Cleaning Validation: A Practical Approach," Interpharm Press, 2000.
6. Health Products and Food Branch Inspectorate, "Good Manufacturing Practices - Cleaning Validation Guidelines," Spring 2000.
7. Destin A. LeBlanc. "Equipment Cleaning Validation: Microbial Control Issues," Journal of Validation Technology, Volume 8, Number 4, August 2002.
8. Herbert J. Kaiser and Maria Minowitz. "Analyzing Cleaning Validation Samples: What Method?" , accessed July 16,2003).
9. Code of Federal Regulations Title 21, Volume 4, Section 211.67, April 2004.

CHECKLIST-VALIDATION OF VENDORS FOR COMPUTER SUPPLY

1.0 Company Information

1.1 Human and Financial resources.

1.2 Knowledge of GMP requirements

1.3 Organization

a) Structure

b) Responsibilities.

1.4 Customer Support

a) Installation and service.

b) Technical support

c) User training.

2.0 Quality System –General.

2.1 Management’s stated policy and commitments.

2.2 Quality group’s responsibility and authority.

2.3 Written Company quality plan.

2.4 Management Review of quality system.

3.0 Quality System –Software Development.

3.1 Development Plan

a) Functional Requirements.

b) Software design specifications.

c) Programming standards and procedures.

d) Programming tools.

e) Review procedures.

3.2 Test Plan

a) Types of Tests.

b) Test tools and methods.

c) Error correction and re-test.

d) Test review.

e) Acceptance criteria.

f) Test reports.

3.3 Configuration Management.

a) Organization and responsibilities.

b) Identification and traceability.

c) Configuration tools.

d) Change control procedures.

e) Version identification control policy.

f) Release approval procedures.

g) Configuration history and status report.

3.4 Program Documentation

a) Source code.

b) Logic diagrams.

c) List of all inputs and outputs.

d) List of all modifiable parameters.

e) List of all operator inputs.

f) Description of interfaces to other systems.

g) Description of alarms and interlocks.

h) Description of error detection and recovery.

i) Description of all data displays.

j) Description of all reports.

3.5 Document Control

a) Documents to be controlled.

b) Approval of issue procedures.

c) Change control procedures.

d) Retention and security procedures.

3.6 Personnel Qualification

a) Formal education.

b) Internal training.

c) Experience in software development.

d) Experience with specific programs used.

e) Experience with application.

4.0 Product Information

4.1 Validation Features.

a) Security.

b) Self documentation.

c) Automatic program change audit trail.

d) Simulation capability.

e) Program compare.

f) Revision documentation detail.

4.2 History of Use

a) Customers of all version.

b) Customers of present version.

c) Configuration history and status report.

4.3 Expected File

a) Present version

b) Revised products.

4.4 Revision Policy

a) Notification of problems.

b) Change required to fix problems.

c) Change to add or modify features.

d) Notification of revisions.

e) Support old versions.

VALIDATION OF COMPUTER SYSTEM

1.0 Describe and Define the system.

a) Describe the Purpose of the System.

b) List the equipment Hardware.

- In-house identification number.

- Merchandising number or name.

- Manufacturer’s Name, Address and Phone Number.

- Hardware serial number, firmware revision Number.

- Date received in the laboratory, date placed in service.

- Location.

c) List of Computer Hardware.

- Manufacturer’s Name.

- Model, Serial Number.

- Processor, Coprocessor

- Memory (RAM), graphics adapter.

- Hard Disk.

- Interfaces, Network.

d) List all software loaded on the computer software with product number, version number and the name of the vendor.

- operating System, User Interface.

- Craned standard Software.

- User specific application software, e.g. MACROs, with date and Size.

e) List accessories such as cables, spare parts etc.

f) Find and review of develop system drawings.

g) Define operator requirement.

h) Define all required functions and operational limits of the modules and system as used for the current application.

- for equipment hardware.

- For the software and for system functions.

i) Define Physical and logical security requirements, e.g. Physical or Password access.

2.0 Collect Any Documentation Available.

a) Reports from internal users on number and type of problem.

b) Reports form external users on number and type of problem.

c) Purchase Order.

d) Certificates and specifications form the vendor.

e) Information on what formulae is used for calculations.

f) Operating Procedures, for example, for basic operation, maintenance, calibration and testing of the system.

g) User manuals.

3.0 Collect Information on System History.

a) Installation Reports.

b) Information on acceptance testing.

c) System Failure Reports.

d) Equipment hardware and system maintenance logs.

e) Maintenance Records.

f) Calibration Records.

g) Result of module and system performance checks.

h) Records on operator qualifications.

4.0 Evaluate past and current system performance and document results.

Evaluate information and documentation collected under item 2 & 3.

a) Check if documentation as collected under 2f and 2g is complete and up to date; for example, does the revision of the existing user manual comply with firmware and software revision numbers?

b) Check if there is evidence of software development validation. Qualification criteria are availability of type and number of documents list under 2d.

c) Check if the equipment (hardware) has been identified for proper and up-to-date functions over the anticipated operating ranges as specified in 1h. Generate a matrix with equipment functions as defined in 1h versus results of calibrations and performance checks as defined in 1h.

d) Check if the computer system has been qualified for proper and up-to-date functions over the anticipated operating ranges as specified in 1h. Generate a matrix with system functions as defined in 1h versus results of acceptance testing. Check if calculations made by the computer software have been verified.

e) Check if the computerized system is suitable for its intended use as specified in 1h. Generate a matrix with performance requirements as defined in 1h versus results of system tests.

f) Check if the system is secure enough to meet the security requirement specifications as specified in 1i. Check also if the security features have been verified sufficiently.

g) Check if the system and type of errors reported under 3c indicates continuous functioning of the system.

h) Check if the operators were / are qualified for their jobs.

i) Prepare an evaluation report. Make a statement on past and current validation status; whatever the system is formally validated (if not define what changes to the system are needed); and make proposals for further validation steps for future use of the system.

5.0 Prospective Validation for Future Use

a) Update or develop system description, user requirement specifications, operating ranges, user manuals, appropriate SOPs and safety procedures as necessary.

b) Update or develop and implement a test and verification plan for the equipment.

The plan should be developed to verify the performance of the various equipment parameters over the anticipated operating ranges and should include documented test procedures, expected results and acceptance criteria. After the test phase a formal report that documents the results should be generated.

c) Update or develop and implement an operator qualification plan.

d) Update or develop and implement a preventive maintenance plan.

e) Update or develop and implement a calibration schedule and /or a performance verification schedule.

f) Update or develop and implement a procedure for annual system review.

g) Update or develop and implement an error recording, reporting and remedial action plan.

6.0 Approvals

The validation plan, the system definition, the result of the past and current evaluation, the prospective validation plan and the test plans and results should be approved and signed by the users and quality assurance departments.