Pharmaceutical Cleaning Validation Method References for Alconox, Inc. Detergents

A cleaning validation involves testing for acceptable residues on pharmaceutical manufacturing or medical device surfaces. The validation involves residue identification, residue detection method selection, sampling method selection, setting residue acceptance criteria, methods validation and recovery studies, and finally writing a procedure and training operators. This procedure is used to document acceptable residues 3 or more times and then a rational monitoring program to maintain a validated state is put in place. If you are changing any part of your procedure or cleaner, first clean the new way, collect data and then clean the old way before using any equipment while you are in the process of validating the new procedure.

Residue identification - in a pharmaceutical manufacturing environment involves; the cleaner, primary ingredients, excipients, decomposition products, and preservatives. This document is intended to help with the cleaner residue identification.

Residue detection method selection - for cleaners can involve specific methods for specific cleaner ingredients such as; high performance liquid chromatography (HPLC), ion selective electrodes, flame photometry, derivative UV spectroscopy, enzymatic detection and titration, or it can involve non-specific methods that detect the presence of a blend of ingredients such as: total organic carbon, pH, and conductivity. The FDA prefers specific methods, but will accept non-specific methods with adequate rationales for their use. For investigations of failures or action levels, a specific method is usually preferable. The later section of this document lists references to several methods for each cleaner brand.

Sampling method selection - for cleaners involves choosing between rinse water sampling, swabbing surfaces, coupon sampling, or placebo sampling. Rinse water sampling involves taking a sample of an equilibrated post-final rinse that has been recirculated over all surfaces. Rinse samples should be correlated to a direct measuring technique such as swabbing. Swabbing involves using wipe or swab that is moistened with high purity water (WFI) that is typically wiped over a defined area in a systematic multi-pass way always going from clean to dirty areas to avoid recontamination - ie. 10 side by side strokes vertically, 10 horizontally and 10 each with the flip side of the swab in each diagonal direction. For TOC analysis very clean low background swabs or wipes and sample vials such should be used. The Texwipe large Alpha Swab 714A or 761 have been used, these are available in kits with clean sample containers. Quartz glass fiber filter papers have been used successfully. Coupon sampling involves the use of a coupons or an actual removable piece of pipe that is dipped into high purity water to extract residues for analysis. Placebo testing involves using placebo product and analyzing for residues from the previous batch.

Setting residue acceptance criteria - in pharmaceutical and medical device manufacturing requires setting residue acceptance levels for potential residues such as the active drug, excipients, degradation products, cleaning agents, bioburden and endotoxins. These levels are determined based on potential pharmacological, safety, toxicity, stability, and contamination effects on the next product using that surface or equipment. Limits are typically set for visual, chemical, and microbiological residues.

The cleaning agent limits are generally covered under chemical criteria. Chemical limits can be expressed as a maximum concentration in the next product (ug/ml), amount per surface area (ug/cm2), amount in a swab sample (ug or ug/ml), maximum carryover in a train (mg or g), or concentration in equilabrated rinse water (ug/ml). You should have a calculated safety based acceptance limit, and you can have a lower internal action level, and a lower process control level based on actual manufacturing and measuring experience.

Cleaning agent safety based limits are typically calculated from a safety factor of an acceptable daily intake (ADI), a (1/1000 or more) reduction of an LD50 preferably by the same route of administration, or reproductive hazard levels. If the calculated limit is found to be higher than a less than 10 ppm carryover to the next batch, then the limit can be set to the more stringent 10 ppm carryover level for the safety based limit.

Calculated safety based limit in mg/cm2 or mg/ml of cleaner residue on a just cleaned equipment:

Limit (mg/cm2 or L) =	ADI carryover - see below (mg) X Smallest Next Batch (kg) Size of Shared Equipment (cm2 or L) X Biggest Daily Dose or of Next Batch (kg)
ADI carryover (mg) =	LD50 by administration route (mg/kg) X body weight (kg) X (1/ 10,000 or 1/1000*)
Comparison calculation of limit based on no more than 10 ppm carryover:
Limit (mg/cm2) =	10 mg residue on just cleaned surface X Next Batch Size(kg or L) 1 kg of L of next product X Size (cm2 or L) shared equipment
* conversion factor used to convert LD50 to acceptable daily intake, use higher number for low LD50s

Note that for many residues you can validate a visual detection limit on the order of 1-4 ug/cm2. It is possible that the visually clean criteria will be the most stringent criteria.

For example with a cleaner that has an rat oral LD50 of over 5 g/kg, the ADI calculation using a70 kg person and a safety factor of 1000 gives a result of 350mg (5 g/kg X 70 kg / 1000 ). The calculated residual acceptance limit for a 2000 kg mixer and line where there might be a next smallest batch of 1000 kg, and the area of the mixer and filling equipment which is all used in the next batch is 100,000 cm2 and the daily dose of the next product is 0.005 kg results in a calculated residual acceptance criteria of 700 mg/cm2 (350 mg X1000 kg/(100,000 cm2 X 0.005 kg). By comparison, the 10 ppm in next batch limit gives an acceptance criteria of 100 ug /cm2 (10 mg X 1000 kg/(1 kg X 100,000 cm2) X 1000ug/mg. In this case, it is likely that you will be able to show that you can visually detect down to 4 ug/cm2 and since you need to have a visually clean surface, your most stringent acceptance criteria will be the visual limit.

Note that in this example you are trying to avoid getting more than 350 mg of residue in a daily dose of the next product. In the case of small final filling equipment such as filling needles for vials or tablet punches and dies, you might need to do separate residue studies on the filling needles or punches to be sure that there was not enough residue just on that equipment to contaminate the first few bottles or tablets of the next batch with a residue of 350 mg/daily dose.

If the safety based limit in this example is set at 100 ug/cm2. Then this limit can be expressed as a rinse water concentration of 100 mg/L in a post final rinse using 100 L of recirculated to equilibrium rinse water (0.1 mg/cm2 X 100,000 cm2/100 L). This same limit could be expressed as 6.25 ug/ml or ppm total organic carbon (TOC) in a sample for a residue that is 10% TOC by weight in a 20 ml swab sample from a 25 cm2 swab area where 50% recovery has been established ((25 cm2 X 100 ug/cm2) X 50% recovery) X 10% TOC/20 ml. The same safety limit can be expressed several different ways.

The methods validation and recovery study - is the use of the sampling and detection method on known spiked surfaces at representative levels, typically spiked at 50%, 100% and 150% of the acceptable limit and at lower expected actual levels to show linearity with documented % recovery as analyzed and to determine the limit of detection and limit of quantitation. Ideally the expected values and limits should be multiples of the limits of quantitation. The % recovery is used to correlate amount detected with amount assumed to be on the surface as an acceptable residue. This is a good time to consider wipe or rinse sample storage conditions and time limits to get the sample analyzed. Rinseability profiles showing the complete rinsing of the individual detergent ingredients should be undertaken if the solubility of any detergent ingredients or the rinseability after drying is in doubt. In some cases bioburden/endotoxin levels may need to be validated. It is recommended that this process be done separately from the cleaning process so that the cleaning validation can be completed while the lengthier bioburden/endotoxin evaluation is done.

The written procedure and training of operators - involves writing out assigned responsibilities, protective clothing needs, equipment disassembly needs, monitoring procedures, documentation needs, labeling of in process and cleaned equipment with cleaning expiration date, post cleaning inspection procedures, storage conditions, and inspection required before next use. The operators then need to be trained and certified in the procedures.

Directory of cleaner residue detection methods for each Alconox detergent:

ALCONOX® :	IV A, C, D, F, and G
LIQUI-NOX® :	IV A, B, C, F, G and I
TERG-A-ZYME® :	IV A, C, D, E, F and G
ALCOJET® :	IV D, F and G
ALCOTABS® :	IV A, C, F and G
DET-O-JET® :	IV D, F, G and I
DETERGENT 8® :	IV F and J
CITRANOX® :	IV A, B, C, D, G and H
LUMINOX® :	IV F and J
CITRAJET® :	IV F and H

A. Anionic surfactant analysis methods for ALCONOX^®, LIQUI-NOX^®, TERG-A-ZYME^®, ALCOTABS^®, and CITRANOX^®. Note that the anionic surfactant is present at approximately 20% by weight in each of these detergents, except Citranox it is present at 3-5%.

1. Chemetrics Inc. water testing kit for anionic detergents, which is sensitive to 1/4 ppm. Contact Chemetrics, Inc. at 1-800-356-3072, or +540-788-9026.
2. LaMotte Chemical water testing kit for anionic detergents, which is sensitive to 1 ppm. Contact LaMotte Chemical at 1-800-344-3100, or +410-778-3100
3. Hach Company water testing method for anionic detergents, which is sensitive to 1 ppm. Contact Hach Company at 1-800-227-4224 or 303-669-3050.
4. A gradient HPLC method in "Journal of Chromatography," 302, (1984) 65-78 by Bear, Lawley and Riddle, Separation of Sulfonate and Carboxylate mixtures by ion exchange HPLC.
5. A "Synthetic Anionic Ingredient by Cationic Titration" method from ASTM D 3049-75 (reapproved 1962) which has been reported to us as having a detection limit on the order of 10 ppm using normalities of 0.004 N Hyamine. It has been suggested that using lower normality Hyamine would give lower detection limits.

B. Nonionic surfactant analysis - the detectable levels are LIQUI-NOX contains roughly 3-7% and CITRANOX contains roughly 1-5% detectable nonionic.

1. An isocratic HPLC method: Schifflet, Shapiro, Levin, and DeNisco "Validation of a Reversed-Phase HPLC Method to Determine Residual Nonoxynol-9 on Pharmaceutical Process Equipment Using a 1.5 µ Nonporous Silica (NPS) Column" to be published circa March 2000 in LC/GC.

C. Direct UV/Visible determination:

1. Direct UV/Visible determination by making a broad-spectrum scan of the detergent to determine a maximum absorbed wavelength. Make standard dilutions of the detergent you wish to analyze for, using 1ppm, 2ppm, 4ppm, 8ppm and 16ppm dilutions. Then measure their absorbence at the maximum wavelength to derive a standard curve against which you analyze the unknown sample from the rinse water or the wipe extract to determine if there is any residue. It has been reported to us that LIQUI-NOX^® has a maximum absorbence at 196-197 nm with a secondary maxima at 225-226 nm and that TERG-A-ZYME^® has a maximum absorbence at 192-193 nm. The reported detection limits were 1-2 ppm. The other detergents, ALCONOX^®, ALCOTABS^®, and CITRANOX^® should be detectable at 196-197 nm and 225-226 nm secondary wavelength.

D. Phosphate detection methods for the complex polyphosphates present in ALCONOX^®, ALCOJET^®, TERG-A-ZYME^®, DET-O-JET^® and ALCOTABS^®. Note that the content of phosphate expressed as %P is printed on the containers of the detergent. Note that these methods test for ortho-phosphate. The polyphosphates present in the detergents are acid hydrolyzable to ortho-phosphate by adding 10% of the sample volume amount of 5 N sulfuric acid and boiling gently for 30 min.

1. American Waterworks Association vol. 57 p. 917-926, 1965 by Edwards, Molof and Schneeman, Determination of Orthophosphate in Fresh and Saline Waters.
2. Hach Company phosphate analysis methods and kits. Call Hach Company at 1-800-227-4224 or 303-669-3050.

E. Protease enzyme detection method for TERG-A-ZYME^® detergent:

1. "Assay in Enzymatic Processing of Food Proteins: II. Method for Detection of Residual Proteolytic Activity" IB number 195a-GB April 1979 from Novozyme, contact them at Tel: 919-494-3000 or www.novozymes.com.

F. Total Organic Carbon (TOC) analysis has been reported to detect the organic surfactants present in ALCONOX^®(11% w/w), LIQUI-NOX^®(21% w/w), (TERG-A-ZYME® 11% w/w), ALCOJET^®(1.5% w/w), ALCOTABS^®(20% w/w), DETERGENT 8^®(38% w/w), LUMINOXtm(26% w/w) CITRANOX^®(17% w/w) and CITRAJET^® (14% w/w). You must go through the acid neutralization step or use the inorganic carbon channel on the TOC analyzer to account for inorganic carbon.

G. When rinsing with deionized water, it has been reported that conductivity has been used to detect conductive salts present in ALCONOX^®, LIQUI-NOX^®, TERG-A-ZYME^®, ALCOJET^®, ALCOTABS^®, DET-O-JET^®, and CITRANOX^®. Standard solutions of known dilution should be made up to determine the detection limits using your equipment. These limits should be reviewed to see if they are suitable for your requirements.

H. CITRANOX and CITRAJET can be detected by Citric Acid analysis both contain around 15% Citric Acid.

1. HPLC using Bio-Rad HPX-87H column, Bio-Rad Cation H Refill pre-column, 0.01 M H2S04 mobile phase, degas, 52 deg C column, 0.6 ml/min flow, 20 microliter sample loop, Waters Model 401 Refractometer detection.
2. Enzymatic detection - Taraborelli and Upton, "Enzymatic Determination of Citrate In Detergent Products" JAOCS Vol. 52, 1975 (248-251).
3. By derivatization and spectroscopy - Hartford, "Rapid spectrophotometric method for the determination of itaconic, citric aconitic and fumaric acids." Analytical Chemistry, Vol 34, No 3 1962 (426-428).

I. Ion selective electrode or flame photometry to detect potassium in Det-o-jet (appprox 13% by wt) - Standard Methods For the Examination of Water and Wastewater 20th Ed. Section 3-87.

J. Propylene glycol ether detection by GC - DETERGENT 8 and LUMINOX contains roughly 25% by weight dipropylene glycol methyl ether detectable using the the Dow Chemical analytical method DOWM-100765-ME90A June 25, 1990, contact Dow Quality/Methods at 517-636-5602.

This information is presented to help communicate our understanding of how cleaning validation has been carried out in pharmaceutical and medical device processing. The information given here is made without any representation or warrantee, as it is presented for your own investigation and verification. Request a technical bulletin for a chemical description of the ingredients in each Alconox, Inc. detergent.

To speak to a technical representative about cleaning validation, call 914-948-4040 for Malcolm McLaughlin (x160) mmclaughlin@alconox.com .

References:

1. Brewer, Rebecca Designing and Documenting Your Cleaning Validation Program to Meet FDA Requirements, Washington Group International , Philadelphia. presented at Cleaning Validation and Cleaning Processes Feb 1-2 Philadelphia, PA (2001)
2. FDA "Guide to Inspection of Cleaning Validation" (1993)
3. FDA "Guide to Inspection of Bulk Pharmaceuticals Chemicals" (1991)
4. FDA "Biotechnology Inspection Guide" (1991)
5. 21 CFR 211 and Proposed Revisions
6. Fourman and Mullen, "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing" Pharm Technol. 17 (4), 54-60 (1993)
7. Leblanc,"Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products," Pharm Technol 22 (10), 136-148 (1998)
8. Cooper, "Using Swabs for Cleaning Validation: A Review" Cleaning Validation , IVT, p 74-89 (1996)

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Aseptic Process Validation

by Tom Spurgeon

What are the regulatory pressures facing aseptic process validation today and what will they be like over the next few years? An inquiry into existing literature and with current industry personnel reveals a corner of the pharmaceuticals industry driven by a lattice of suggested improvements, a constant hum of activity and improvements that fight to keep pace with general industry trends and emerging technology. Those working in aseptic processing validation must consistently look five years ahead and five years behind, at rules and informative processes and market realities, all of which play off one another like so many strings on a musical instrument. With an important FDA guidance revision just now beginning its long fade into routine and a brand new one described as imminent, aseptic processing and its regulatory outlook is at the forefront of pharma and biopharma business plans.

It's worth noting that the core guidance revisions for aseptic processing validation are still new. "The reason it's a hot area is that we had the aseptic processing guidance that was revised in 2004," said Hal Baseman, chief operating officer and a principal partner at Valsource.

Maurice Phelan, director of Pharmaceutical Technology, BioProcess Division at Millipore Corp., noted that newer statements are driving much of the attention: "The one thing that's gotten everybody interested, and sort of sparked a lot of interest in this subject over the last say year and a half, is the major statements by particularly the FDA about the need to change the way we manufacture sterile products."

Mr. Baseman added, "In September of 2004, there was a revision of the aseptic processing guidance. That resulted in a lot of discussion around validation of aseptic processing and things like that. It's always been a hot issue, an important issue, if you look at it from a risk management perspective. It's certainly a process that gathers a lot of attention."

Mr. Phelan sees the 2004 guidance as even more important in context. "I think it's the 2004 guidance, which was long awaited, but is also the strategic plan that the FDA has laid out, all of the concepts that are embodied in their GMPs for the 21st century initiative. All of the high-level sorts of concepts and aspirations that they have that are laid out in things like the Critical Path Initiative. And then there's the 2004 aseptic process guidance, when it's considered in the context of quality by design, design space concepts, all of the buzz in the industry around efficiency and manufacture, things like process analytical technologies -- when you consider all of those as contributors, then I think the buzz that's around aseptic processing and next generation manufacturing is a result of all of those together, and the context they have for whatever kind of manufacturing you do, whether it's biotech, or classical pharma-type manufacturing. It all depends on your interpretation on what it means to you."

The 2004 revision was the first major one since 1987, and therefore drew attention not just for the new standards it suggested, but for how the revision reflected modern industry practices. The result was a wave of attention to such issues that continues unabated. There are at least two major conferences this autumn that promise discussion of the subject, and specific classes on techniques involving aseptic processing and its validation that are filled weeks in advance. Mr. Phelan noted that there is genuine change reflected in the approach to process validation, within the hierarchy of validation.

He said, "Historically much of the body of work that would be called process validation wouldn't necessarily differentiate between that which was super-critical and that which was a required component but had variability that the process could tolerate. Intuitively the FDA is saying it's not just practical. Intuitively, if you've thought through a rationale that allows you to rank the criticality of unit operations in your process, then there should be a corresponding validation in your unit operations that's increasing in focus and scientific content as you go up the criticality scale. "I've heard an FDA inspector say, ‘Say what you're going to do. Prove that you can do it. And then when you get into manufacturing, do what you say you do.' That's a fairly straightforward statement for these guys to make."

In making its guidance revisions, the FDA gathers information from industry sources and then, once compiled, releases it back, causing a re-affirmation of the industry's best practices distinct, in its way, from standards the FDA might apply to drive companies into certain practices. At one meeting in 2002, the FDA's Advisory Committee For Pharmaceutical Science heard from several industry leaders and its own speakers on a variety of subjects related to aseptic process validation, including container-closure and sterile isolators. As Mr. Baseman put it, "Because we had an opportunity to comment extensively as the FDA allowed us to do [for the 2004 guidance], it became a reflection of what the industry was doing."

That give-and-take continues into the field. Said Mr. Phelan, "I heard this from the FDA as recently as last week: If you want to interact with them, and you're prepared to think about applying some of these next generation concepts, than they want to engage you." This is a change from times past, he noted. "Historically the FDA would have said, ‘Our door is open, and nobody's coming to talk to us. It's a one-way affair for us, and we have no option but assume a worst-case scenario. The only opportunity we have to share information is in the limited capacity of inspections or audits or reviews.' Now they're saying, ‘We have to change the way we do business. It's our view that you, the manufacturing community, need to look at how you manufacture and look at these types of areas.' Quality by design is the classic example of what they'd like to see.

"They've put programs into place," he added. "They have a pilot program that's gone on for the last 12 months for the review of new drug applications, where they've invited people to participate in basically a risk-based construct for the CMC sections in their new drug application."

The Guidance revision not only provides a platform for understanding the FDA's expectation and current industry practices, it also serves as a spur to science by offering up its own set of ways to approach certain problems while fostering from related organizations more up-to-the-minute, specific technical solutions.

With the FDA's more general efforts starting in 2001 to implement GMPs "for the 21st Century" -- itself two decades since the last similar effort -- came an emphasis on risk analysis. Risk analysis became the tool through which managers began to approach the validation of their aseptic processing techniques.

Mr. Baseman explained the general process as it has an impact on a facility's approach to their processing procedures: "Most biological contamination comes from people. So anything involving human intervention is going to be a riskier step. If we're doing an aseptic process test, let's say there's a step in there where somebody has to add a component manually, like a stopper. That becomes a riskier step. If we can eliminate that step by having some automated system to do that, then we eliminated and improve the process. That pushes us towards using isolators rather than conventional filling lines." The prioritization that comes with risk-management engenders a step-by-step vetting of the process validation. It puts emphasis on key points such as filtration, and then works its way backward to elements with less of a risk. As risk-management works its way to and then through those industry agents that have yet to fully embrace that approach, their use should become more and more routine.

This is just the way the FDA wants it, said Mr. Phelan. "Classically, validation exercises have been very, very document-heavy exercises. The FDA are now saying that we think there's a very practical approach to be taken in addressing all of the validation that needs to be done in a manufacturing process, assessing what the risks and/or overarching benefits are to putting so much effort into that enormous body of work, and then maybe thinking about a different way of justifying the amount of focus you put on in respect to validation, exercises based on their risk to your program."

Despite the fact that ideal sterilization technique is terminal, or heat-based, the market should drive more and more companies into aseptic processing. As most are quick to point out, terminal sterilization is a poor technique to apply to unstable products such as those represented by protein-based drugs. Aseptic processing places a specific emphasis on filtration as the last process performed to destroy organisms or contamination within a product. "Filtration would be where you would take the product, put it through a .2 micron filter and then fill it under very controlled conditions, in a clean room, perhaps in an isolator or perhaps in a conventional clean room but one with a lot of controls to keep the contamination out of the product," said Mr. Baseman. "Because there will be no subsequent step to destroy those organisms. That's why filtration is of interest related to aseptic processing."

With technology, market concerns and the introduction of new techniques and practices all driving interest in aseptic processing and its validation, one might think of the regulatory backbone as one of pressure and punishment. Actually, the opposite seems closer to the truth. Mr. Baseman praised the FDA for its ability to solicit commentary when preparing its guidances, both from individual players and major industry organizations like the Parenteral Drug Association (PDA). Not only does this give them a wider array of knowledge to use, the process settles industry players for whatever changes are to come. "I believe it's rare for the FDA to come out with something that's a big surprise," said Mr. Baseman. "For the most part what happens is that guidance gets issued that reflects what the FDA has been talking about and what the industry has been doing.

"I think there's an anticipation, but I don't think people are sitting there saying, ‘Maybe we shouldn't do any process validation this year because everything is going to change.' I don't think that's the case. The FDA has done a good job indicating where it's heading with this. They certainly put out some pretty good information in their initiative documents. There was a CPG that came out I think last year, but that CPG -- and that's their internal guidance document -- talked about what the agency would internally be looking for when it reviewed submissions. So if you read that, you kind of understood what the Agency is looking to do."

Groups like the PDA provide further support by issuing technical reports following guidances and standards, reports that provide a very specific way of meeting required standards, to be accepted, used or even refused, and make more clear the science of what's being done, away from purely regulatory motivations. For instance, PDA Technical Report #42 deals specifically and in what is described as a "practical" fashion with Process Validation in terms of protein manufacturing.

This system of multiple supports and reinforcements sets the stage for a revised guidance from the FDA for processing validation. Mr. Phelan characterized such revisions as "imminent." As to what that revision will entail, Mr. Baseman opined, "I think it may have something to do with new techniques. There's so much new technology that's coming out now, and I think it's important that the PDA weigh in on new technology, things down the road: new technologies for monitoring and so forth."

Mr. Phelan thinks the emphasis will be on the principles driving multiple solutions. "What I would expect is that it will contain all the intellectual components that one would classically associate with process validation and then it will have loaded on top of those good validation practices the concepts of design space, critical process parameters, risk-based decision-making and then practical validation approaches -- a rationale that says I understand what drives my process and I understand the critical parameters I need you to control and I need to validate.'"

As more companies are driven to work with drug forms that resist terminal sterilization, those that embrace GMPs and a risk-based outlook should find strong support in terms of aseptic process validation techniques, applied to steps ranging from filtration to use of isolators to air flow, that match the criticality of each phase to their overall function. Look for future guidance and technical papers to build on rather than replace the general outlook, at least until it becomes routine, as all former hot topics must sooner or later.

Validation and verification

Validation and verification are important to establish that components within the
water safety plan are working as expected and that the water safety plan as a whole is
delivering the required results.
11.1 VALIDATION
Validation should be targeted at the assessment of the scientific and technical inputs
into the water safety plan. Validation should ensure that the information supporting
the plan is correct and that the elements
of the water safety plan will be
effective, thus enabling conformity with
health-based targets (see Chapter 12)
and public health policy.
Process validation is required to
show that treatment processes can operate as required. It can be undertaken during
pilot stage studies, during initial implementation of a new or alternative water
treatment system and is a useful tool in the optimisation of existing treatment
processes. Table 11.1 details the validation of the critical limits, relating to
coagulation and flocculation, for the Molendinar water purification plant, operated by
Gold Coast Water (Australia),Evidence for validation of the water safety plans can come from a variety of
sources, including the scientific literature, trade associations, regulation and
legislation departments, historical data, professional bodies or supplier knowledge.
This can inform subsequent testing requirements, including the use of specific
pathogens or indicator microorganisms. Microbial parameters, such as heterotrophic
plate counts and coliform enumeration, which may be inappropriate for operational
monitoring, can be used for validation purposes and the design of treatment systems
as this does not form part of the routine day-to-day monitoring and management and
thus the lag time in receiving the results is not a problem.
11.2 VERIFICATION
Verification may include review of monitoring control measures, microbiological and
chemical testing, or review of the water
safety plan overall to ensure that it is
still accurate. This may be necessary,
for instance, if there have been changes
to processes or equipment.
To verify system performance, periodic checks are necessary.
11.2.1 Microbial water quality
For microbial quality, verification is likely to include some microbiological testing. In
most cases it will involve the analysis of faecal indicator microorganisms (for further
details see Dufour et al. 2003), but in some countries it may also include assessment
of specific pathogen densities. Verification for microbial quality of drinking-water
may be undertaken by the supplier, surveillance agencies or a combination of the two.
Approaches to verification include testing of source water, treatment end-point
product and water in distribution systems or stored household water. Verification of
microbial quality of drinking-water includes testing for Escherichia coli as an
indicator of faecal pollution. E. coli provides conclusive evidence of recent faecal
pollution and should not be detected. In practice, the detection of thermotolerant
coliform bacteria can be an acceptable alternative in many circumstances. While E.
coli is a useful indicator it has limitations. Enteric viruses and protozoa are more
resistant to disinfection and consequently the absence of E. coli will not necessarily
indicate freedom from these organisms. Under certain circumstances it may be
desirable to include analysis for more resistant microorganisms such as
bacteriophages and/or bacterial spores. Such circumstances could include the use of
source water known to be contaminated with enteric viruses and parasites or high
levels of viral and parasitic diseases in the community.
Water quality can vary rapidly and all systems are subject to occasional failure. For
example, rainfall can greatly increase the levels of microbial contamination in source
waters and waterborne outbreaks often occur during and shortly after storms. Results
of analytical testing must be interpreted taking this into account.
11.2.2 Chemical water quality
Assessment of the adequacy of the chemical quality of drinking-water relies on
comparison of the results of water quality analysis with guideline values. For
additives, i.e., chemicals deriving primarily from materials and chemicals used in the
production and distribution of drinking-water, emphasis is placed on the direct control
of the quality of these products. In controlling drinking-water additives, testing
procedures typically assess the contribution of the additive to drinking-water and take
account of variations over time in deriving a value which can be compared with the
guideline values.
Some hazardous chemicals that occur in drinking-water are of concern because of
effects arising from single exposures or sequences of exposures over a short period.
Where the concentration of the chemical of interest varies widely, even a series of
analytical results may fail to fully identify and describe the public health risk. In
controlling such hazards, attention must be given to both knowledge of causal factors
and trends in detected concentrations, since these will indicate whether a significant
problem may arise in the future. Other hazards may arise intermittently, often
associated with seasonal activity or seasonal conditions. One example is the
occurrence of blooms of toxic cyanobacteria in surface water.
11.4 KAMPALA CASE STUDY – VALIDATION AND
VERIFICATION
In Kampala, a risk assessment was performed on the system to assess current
performance and as a means of validating whether the water safety plan would deliver
water considered safe (Howard and Pedley 2003). The assessment took the form of
assessment of removal of selected microbial indicators and index organisms through
the treatment works (E.coli, Clostridium perfringens and coliphage) and analysis of
indicator organisms (E.coli and faecal streptococci) in the distribution system. A
quantitative risk assessment was performed, using a well-defined set of assumptions
regarding the relationship between organisms analysed and pathogen groups. The
process utilised the simplified methodology outlined in the WHO Guidelines for
Drinking-Water Quality, 3rd edition (WHO 2004).
The assessment demonstrated that effective implementation of the water safety
framework ensured adequate bacterial quality from the treatment works, although as
the source water was of high quality this was expected. The assessment demonstrated
that risks were much greater in the distribution system and therefore emphasised the
need for improved safety management within the network following the water safety
plan.
The assessment did indicate that the treatment works provided far less security
regarding the risk from protozoan pathogens, a result again expected given that the
plants were not designed with protozoa removal in mind. It was concluded that
greater security could be obtained in one treatment works through better operation,
but in the second investment would be required to upgrade the system. However,
bearing in mind that overall rates of connection were low, alternative supplies were
grossly contaminated and that poor hygiene and inadequate sanitation were likely to
account for a greater proportion of pathogen transmission, it was recommended that
such investment was a relatively low priority.
Verification is achieved through a number of mechanisms. At the treatment works,
a regular programme of testing for E.coli was established (following previous
practice, but with reduced frequency) and the laboratory was equipped to perform
analysis of Clostridium perfringens as a means of testing treatment efficiency.
Treatment plant audits are also undertaken on a regular basis to review operational
records.
A rolling programme of testing for E.coli and sanitary inspection is also
implemented for the distribution system. Periodic testing of faecal streptococci is also
performed. These processes provide the water quality control department with data on
which to ensure that the water safety plan is delivering safe drinking-water and can be
incorporated into periodic risk assessments using available data.

Cleaning Validation Protocol

CLEANING VALIDATION

1. Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products.

2. Pharmaceutical products can be contaminated by other pharmaceutical products. The objective of cleaning validation is the confirmation of a reliable cleaning procedure so that contamination is reduced to predetermined levels.

3. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts.

4. Cleaning procedures for product formulation changeover should be validated.

5. Generally in case of batch-to-batch production of the same product, it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined as appropriate.

6. Cleaning procedures for products and processes which are very similar do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".

7. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. Control of change to validated cleaning procedures is required. “Testing until clean” is unacceptable.

8. Operators carrying out manual cleaning procedures should be adequately supervised Dedicated equipment may be necessary for products which are difficult to remove, for equipment which is difficult to clean, or for products with a high safety risk.

9. The existence of conditions favorable to microorganisms and the time of storage should be considered. The period and, when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

10. Samples should be taken according to the cleaning validation protocol. The choice of sampling methods should be demonstrated to provide accurate information about the effectiveness of the cleaning process.

11. Two methods of sampling considered to be acceptable are direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods may be desirable in circumstances where accessibility of equipment can mitigate against direct surface sampling.

12. The suitability of the material to be used for sampling and of the sampling medium should be determined to assure predetermined levels of recovery.

13. Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples. A direct or indirect measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.

14. Other techniques which may be used include coupon sampling, solvent sampling, product sampling, placebo sampling and direct surface monitoring.

15. If cleaning agents are used, acceptable limits should be defined for residue of the agent after cleaning.

16. Analytical methods should be validated.

17. Analytical methods used to detect residuals or contaminants should be appropriate for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable.

18. The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery.

19. The rationale for selecting limits for product residues should be based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.

20. One cannot ensure that the contaminant will be uniformly distributed throughout the system. It is also invalid to assume that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.

21. In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.