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Microbial Aspects in Cleaning Validation

  • Center for Pharmaceutical Cleaning Innovation, LLC

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This chapter will discuss microbiology as it pertains to Cleaning Validation. In practice, the primary focus of Cleaning Validation is the removal of chemical residues, either from active ingredients or cleaning agents, and microbiological issues are of an incidental nature. It should be understood that the purpose of cleaning procedures should never be seen as being used to reduce microbial residues to acceptable levels.
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Chapter 9
Microbial Aspects in Cleaning Validation
Andrew Walsh, M.S., Industry Professor, Stevens Institute of Technology, Hoboken, NJ, USA,
President, Clean6Sigma, LLC
9.1 Introduction
9.2 Regulatory Aspects of Cleaning
9.2.1 API Manufacturing
9.2.2 Finished Pharmaceuticals
9.2.3 Cleaning Processes
9.3 Cleaning Agents
9.4 Cleaning Procedures
9.4.1 Manual Cleaning
9.4.2 Clean-Out of-Place (COP)
9.4.3 Clean-in-Place (CIP)
9.5 Solid Dosage Forms
9.5.1 Setting Microbial Acceptance Criteria for Solid Dosage Forms
9.6 Semi-solid Dosage Forms
9.6.1 Setting Microbial Acceptance Criteria for Semi-solid Dosage Forms
9.7 Hold Time Studies
9.8 Microbial Testing in Cleaning Validation
9.9 Conclusion
9.10 Acknowledgements
9.11 References
This chapter will discuss microbiology as it pertains to Cleaning Validation. In practice, the
primary focus of Cleaning Validation is the removal of chemical residues, either from active
ingredients or cleaning agents, and microbiological issues are of an incidental nature. It should
be understood that the purpose of cleaning procedures should never be seen as being used to
reduce microbial residues to acceptable levels. Many companies have mistakenly claimed this
in Cleaning Validation Policies and Cleaning Validation Protocols. Logically, if microorganism
residues on equipment were at an unacceptable level prior to cleaning, then this implies that
the batch just made must have been contaminated. Hopefully this is never the case.
Many products are required to be sterile and some products are unacceptable even if
microorganisms are present at low levels. For these products, manufacturing equipment that
has been cleaned must also be sterilized or sanitized prior to manufacturing use and this
typically takes place shortly after cleaning is completed. For example, sterile injectable
products would fall into this category. Sterilization and sanitization procedures are focused on
the elimination or reduction of microorganisms and are separate from cleaning procedures and
therefore not part of this chapter. Although endotoxin may be a concern for injectables if high
levels of microorganisms are present after cleaning, as we shall see this is typically not the case.
Cleaning Validation also focuses only on the “product contact surfaces” of manufacturing
equipment and does not involve the cleaning and sanitization of floors, walls or other “non-
product contact surfaces”.
Many other products though, such as solid oral dosage forms and semi-solid dosage forms, are
not required to be sterile and their equipment cleaning procedures are not necessarily
followed by any sterilization or sanitization methods. However, while low levels of
microorganisms may be of minimal concern, there remains the possibility that a poorly
designed, or improperly executed, cleaning procedure may present conditions that encourage
the growth of microorganisms on the equipment surfaces. Also, the presence of certain
microorganisms may be objectionable in any case. Because of the potential for microbial
proliferation on equipment due to cleaning procedures and subsequent product
contamination, microbiological testing is normally included in Cleaning Validation studies. This
chapter will explore the significance of microbiology in these dosage forms after cleaning.
The Code of Federal Regulations for the cGMPs of Finished Pharmaceuticals, 21 CFR Part 211,
contains a section under Subpart D - Equipment that specifies:
Sec. 211.67 Equipment cleaning and maintenance Subpart (a) “Equipment and utensils
shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized
and/or sterilized at appropriate intervals to prevent malfunctions or contamination
that would alter the safety, identity, strength, quality, or purity of the drug product
beyond the official or other established requirements.”
It is from this section that the requirement for Cleaning Validation has evolved. Other
regulatory agencies have GMP guidance with similar requirements (2-4) mandating that
manufacturing equipment be cleaned and maintained in ways that will prevent cross-
In the late 1980s FDA’s concerns over the cleaning of manufacturing equipment began to
escalate due to several incidences where cross contamination actually occurred, or where the
risks of cross contamination were found to be unacceptable. During this time, pharmaceutical
companies began various activities to satisfy FDA’s growing GMP expectations around cleaning.
Then in 1992, the U.S. vs. Barr Laboratories case addressed several aspects concerning the
need for cleaning validation and Judge Wolin’s decision solidified cleaning validation as a GMP
As part of his ruling in the Barr case Judge Wolin criticized the FDA for being ambiguous and
vague in what FDA’s requirements for GMP were. (5) Indeed, the GMPs are not very specific. In
1993 FDA issued their Guide to Inspections: Validation of Cleaning Processes” to guide FDA
inspectors during their inspections and to clarify their expectations of industry on cleaning and
cleaning validation. This guide makes it clear the FDA’s concerns involved drug (chemical)
residues stating that “This guide is intended to cover equipment cleaning for chemical residues
only.” However, the guideline later directs inspectors that:
“….microbiological aspects of equipment cleaning should be considered. This consists
largely of preventive measures rather than removal of contamination once it has
occurred. There should be some evidence that routine cleaning and storage of
equipment does not allow microbial proliferation. For example, equipment should be
dried before storage, and under no circumstances should stagnant water be allowed to
remain in equipment subsequent to cleaning operations.”
Although microbiology is not a major regulatory concern in cleaning validation, there are a
number of areas during cleaning where microorganisms pose a potential concern for product
quality and therefore have importance from a GMP perspective and these areas do need to be
addressed during cleaning validation. (6-7) In 2003, the FDA promulgated their newer
perspectives on GMPs and product quality called “Pharmaceutical GMPs for the 21st Century”
(8) where activities such as validation (including cleaning) should be “science-based” and “risk-
based”. The following sections will discuss microbiology in cleaning validation within the
context of “science” and “risk”.
9.2.1 API Manufacturing
Most pharmaceutical APIs are manufactured using organic solvents and the cleaning
procedures for API equipment typically involve “boil-outs and washes often with the same
organic solvents used in the APIs manufacture. The use of organic solvents would preclude
microbial contamination from the cleaning procedure as most of these solvents have
antimicrobial properties. The manufacture of biological APIs involves water and microbial
proliferation is a concern. However, their cleaning procedures are followed by Steam-in-Place
(SIP) sterilization processes or other such processes to eliminate any traces of microorganisms.
Currently there are movements in the API industry to replace organic solvents in the cleaning
process due to environment, regulatory and cost reasons. Aqueous cleaning procedures are
being examined for substitution of solvents (9) and these raise the possibility of microbial
growth and contamination for these APIs.
9.2.2 Finished Pharmaceuticals
The Finished Pharmaceuticals present a different scenario. For most of these products cleaning
procedures are not followed by a sterilization step. If microorganisms are left on the product
contact surfaces of their manufacturing equipment, these microorganisms can be readily
introduced into these products. It is important to understand what the significance of this is.
9.2.3 Cleaning Processes
It is important to have an understanding of the cleaning processes used in finished
pharmaceutical manufacturing as it is the nature of the cleaning process itself that dictates
whether a cleaning procedure may cause microbiological concerns.
There are a variety of cleaning agents used for removing residues of finished pharmaceuticals.
(10) One predominant group are cleaners based on the alkalis. Alkalis are destructive to
microorganisms and can be considered bactericidal. Most surfactants have some degree of
bactericidal or bacteriostatic activity, especially the cationic surfactants. Complexing agents
such as EDTA may also be used to help remove inorganic residues. Also, strong oxidizers are
now being used to breakdown or destroy organic residues and these compounds have strong
antimicrobial properties (see Table 9.1).
Types of
Cleaning Agents
Fatty-type soils, protein deposits
Dissolving mineral salts,
removing scale
HCl, HNO3, H3PO4, Citric Acid
Wetting, Suspending Dispersion,
Sodium Dodecyl Benzene Sulphate,
Sodium Lauryl Sulphate
Prevent deposition from scale
EDTA, Nitrilotriacetic acid
Removing organic residues
Sodium Hypochlorite, Hydrogen
Table 9.1: Types of Cleaning Agents
Currently in some facilities, water alone is being used as a cleaning agent under the rationale
that the product constituents are water-soluble so water is sufficient for adequate cleaning.
However, this approach ignores the poor wetting properties of water itself which can lead to
incomplete cleaning and the accumulation of residues on equipment and is a practice that
should be avoided.
There are five steps typical of all cleaning procedures.
Pre-rinse Step This step is used to physically remove the bulk of remaining product from a
piece of equipment. Typically, potable water is used for this step. Potable water may have low
levels of microorganisms in it.
Wash Step This step typically employs some form of a cleaning solution to remove the last
traces of product residues from a piece of equipment. Cleaning solutions are normally made
through dilution of a cleaning agent with water and plant potable water is used to make these
cleaning solutions. Most constituents of cleaning agents have antimicrobial properties
(surfactants, NaOH, HCl, etc.) so the cleaning solutions will generally have lower levels of
microorganisms than the potable water.
Rinse Step - This step is used to remove any cleaning agent residues from the equipment.
Typically, potable water is used for this step. Again, the potable water may have low levels of
microorganisms in it.
USP Water Rinse Step - This step is used to rinse away any residue that may be present in the
waters used for the Rinse step to restore the equipment surface to conditions experienced in
manufacture. USP water is required to be below 100 CFU/mL. FDA and most other regulatory
agencies expect this final step to use the grade of water used in the products manufactured
(i.e., if WFI is used for formulation then the final rinse should use WFI).
Drying Step - This step is used to remove any remaining water on the equipment. This can be
achieved by simple air drying, drying under heat, or spraying with alcohol to accelerate
evaporation of the water.
Although there are many variations on the steps listed above, there are three different
approaches to performing these cleaning steps. Cleaning procedures may be completely
manual to completely automated.
9.4.1 Manual Cleaning
Manual cleaning procedures are typically used on small parts or equipment that is
disassembled for cleaning (e.g., a packaging line). The rinse and wash steps of these procedures
may be performed in sinks or troughs large enough to be capable of holding these parts. A
“soak” step may be used or parts may simply soak as a matter of course while waiting to be
cleaned next. Cleaning solutions are normally used at lower temperatures and sometimes
lower concentrations (e.g., caustic solutions) due to operator safety.
Figure 9.1: Ultrasonic Cleaner Photo courtesy of Amtrex Technologies Inc (
In some cases an Ultrasonic Cleaner is used to aid in dislodging product from equipment parts
(e.g., tablet punches and dies). It should be pointed out that Ultrasonic Cleaners require
cleaning between products to remove product residues and stagnant, warm, dirty cleaning
solutions pose a risk of microbial contamination of parts if the Ultrasonic Cleaner itself is not
properly cleaned.
9.4.2 Clean-Out of-Place (COP)
These procedures are used to clean parts of equipment that are disassembled but are too large
to clean manually in a sink or trough or to clean large pieces of equipment. The equipment is
removed from the manufacturing area and placed in, or on, an apparatus designed to clean the
equipment. These can be elaborate washing cabinets with automatic control systems,
immersion systems with automatic control systems or simple dishwasher type units. These
systems can be automated or run manually step by step. Examples of some equipment cleaned
using COP systems are Intermediate Bulk Containers, Bins, Drums, and Carboys. Cleaning
solutions can be used at higher temperatures and higher concentrations as operators are not
exposed to them.
Figure 9.2: COP System Photo courtesy of Ecolab Inc. (
Some COP systems (e.g., Immersion type) have similar concerns as with Ultrasonic Cleaners and
require cleaning between products to remove any remaining product residues and cleaning
9.4.3 Clean-in-Place (CIP)
These procedures are used to clean equipment that cannot be disassembled or moved, such as
large stationary tanks or bioreactors. The equipment is left in place and a stationary or portable
CIP system or skid is connected to the inlet and outlet of the equipment. CIP systems typically
come with some degree of automatic control and are capable of performing all of the standard
cleaning steps described above automatically or manually step by step. CIP systems use devices
called spray balls, spray rings or spray wands to provide coverage of all internal surfaces in
enclosed equipment. These spray devices are placed into the equipment for cleaning and
removed afterwards. However some systems are built into the equipment they will be cleaning.
As with COP systems, cleaning solutions can be used at higher temperatures and higher
concentrations as operators are not exposed to them. Non-ionic surfactants are typically used
as foaming is a problem in Clean-in-Place Systems and these surfactants are low to non-
Figure 9.3: CIP System Photo courtesy of Ecolab Inc. (
CIP systems provide a savings in time and labor to clean large stationary equipment. Parts of
the CIP system, particularly permanent spray balls and rings, contain areas where water may
collect and allow microorganisms to grow and these may become a concern. Although CIP
systems are designed to provide cleaning through recirculation of rinse and wash solutions, due
to cross contamination concerns most systems are operated in a once-through-to-drain
configuration. While this provides assurance that contaminated rinse or wash solutions cannot
be introduced into cleaned equipment, this approach is costly and wasteful of cleaning
solutions and water.
Solid Dosage Forms are typically dried to very low water content to eliminate the probability of
undesirable hydrolysis reactions and provide the great stability enjoyed by these dosage forms.
An added benefit of this low water content is the inhospitable environment this presents to
microorganisms. All microorganisms require sufficient free water in order to grow. However,
overall moisture content in itself is not a predictor of microbial growth. Another measure,
Water Activity (aW) is a much better predictor of the possibility of microbial growth as it is a
measure of the water available for microorganisms to use for growth. For pharmaceuticals,
Water Activity can be defined as the ratio of the vapor pressure of the air in equilibrium with a
drug product, to the vapor pressure of pure water. Water Activity ranges from a value of 1.0
(for pure water) to 0.0 (no water at all) and, as it is a ratio, it is a dimensionless value. As a
general rule, if a Solid Dosage Form has a Water Activity below 0.6, there can be no microbial
growth in these products even if microorganisms have been introduced through contact with
manufacturing equipment. For products such as these the elimination of microbial testing from
end product testing may be justified. (11,12) So many Solid Dosage forms are not particularly
sensitive to microbial contamination.
9.5.1 Setting Microbial Acceptance Criteria for Solid Dosage Forms
Considering the discussion above it appears that low levels of microorganisms on solid dosage
manufacturing equipment can be considered somewhat insignificant. But at what level would
they not, and what would be an appropriate limit for microorganisms on such manufacturing
equipment? In 1999, Scott Docherty proposed using an approach similar to the one commonly
used for setting chemical residue limits in Cleaning Validation. (13) Docherty noted that many
solid dosage forms have a USP limit of <1,000 CFUs (colony forming units)/gm. Starting with a
finished product limit of 1000 CFU/gm and calculating backwards, Docherty determined how
many microorganisms/cm2 would have to be on the manufacturing equipment surfaces to
result in 100 CFU/gm in the finished product. Let’s examine a typical piece of solid dosage
equipment, a “V” Blender in Table 9.2.
20 ft3 V-Blender
Total product contact surface area = 50,000 cm2
Table 9.2: V-Blender microbial load calculation
As we can see the calculated limit for the number of organisms is extremely high and well
beyond what could be encountered in normal operations. In the article it was felt this was well
beyond what could be considered compliant with cGMPs so the decision was to set limits at 25
CFU/ cm2. However, in today’s “science and risk-based” environment, these “limit” calculations
can be quite useful for determining the risk to patients and products presented by the
microbial levels actually recovered from equipment surfaces during cleaning validation. The
microbial levels recovered can be compared to these calculated limits and a Process
Capability value determined. Such Process Capability values can be used to determine the level
of risk and the criticality of cleaning procedures. Typical microbial data collected from many
cleaning validations may look like those shown in Table 9.3.
Sample Counts (CFU/25cm2)
Number of Samples with that Count
Table 9.3: Sample microbiological data collected during a typical cleaning validation.
Microbial data do not follow the more easily understood normal distribution used in Statistical
Process Control (SPC) calculations and instead follow non-normal “exponential” or “Poisson”
distributions. The following statistical analyses were conducted with the data from Table 2
using an exponential model.
2.5 x10^8/cm2
Target *
US L 2.5e+00 8
Sam ple Mean 0.716592
Sam ple N 446
Me an 0.716592
Process D ata
Pp *
PP L *
PP U 58985362.94
Ppk 589 85362.94
O verall C apability
PP M < LS L *
PP M > U SL 0. 00
PP M To tal 0.00
O bserved P erformance
PP M < LS L *
PP M > U SL 0. 00
PP M To tal 0.00
Exp. O ve rall Performa nce
Process Capability of Data using 2.5x10^8 CFU/25cm2
Calculations Based on Exponential Distribution Model
Figure 9.4: Process capability of data using 2.5 x 108 CFU/25 cm2
This analysis yields a Process Performance capability (Ppk) of 58,985,363. Considering that
Process Capability values are considered acceptable if they are greater than about 1.33 this
2.5 x 10^5/cm2
result is astronomically high. This should be seen as a clear indication that the possibility of
microbial contamination to obtain a level of 1,000 CFU/gm from manufacturing equipment is
highly unlikely, if not impossible. This analysis is not meant to imply that this is an appropriate
way to set microbial limits on equipment surface areas; what we have shown in this instance is
a way of quantifying the level of risk posed by such data to product quality.
Figure 9.5 shows an analysis using the 25 CFU/25cm2 chosen in the Docherty article. As we can
see the Ppk is still quite high at 5.78 (as compared to 1.33) and the risk of failure is still low. Yet
is this an appropriate limit? Docherty goes on to recommend to collect data over a period of
time, evaluate it and then set “....realistic and justifiable limits based upon historical data”. A
typical approach using normal data is to collect data, calculate μ and σ, and then set an upper
limit based on μ + 3σ or 4σ. As stated before microbial data does not follow the normal
distribution; however, there are statistical approaches for setting limits from non-normal
distributions14. It is therefore quite possible to use science and risk-based approaches to setting
limits for microorganisms on manufacturing equipment following cleaning.
25 CFU/ 25 cm2
Target *
US L 25
Sam ple Mean 0.716592
Sam ple N 446
Me an 0.716592
Process D ata
Pp *
PP L *
PP U 5.78
Ppk 5. 78
O verall C apability
PP M < LS L *
PP M > U SL 0.00
PP M To tal 0.00
O bserved P erformance
PP M < LS L *
PP M > U SL 0. 00
PP M To tal 0.00
Exp. O ve rall Performa nce
Process Capability for Data using 25 CFU/25cm2 Limit
Calculations Based on Exponential Distribution Model
Figure 9.5: Process capability of data using 25 CFU/25 cm2
Semi-solid Dosage Forms are also not manufactured sterile and can have significant free water
present so can be quite susceptible to microbial growth. Normally, these products require
preservatives to provide freedom from microbial growth and ensure product quality and
The United States Pharmacopoeia requires that the preservative systems used for these
products be challenged to determine their effectiveness against the possible introduction of
microorganisms. (15) Several common microorganisms are used in these studies including
three species of bacteria, one yeast and one mold. In these “challenge studies”, inoculum levels
of these microorganisms are introduced into these products ranging from 1x103 to 1x105
CFU/mL The products are then tested for microbial content at 7, 14 or 28 days. For the
bacteria, the preservative systems are expected to observe a 1-3 log reduction in
microorganism numbers to pass this “challenge”. While there is much debate over the
significance of these criteria and the interpretation of the results (16), the results of such
testing can be used as a gauge of the significance of microorganism levels on manufacturing
9.6.1 Setting Microbial Acceptance Criteria for Semi-solid Dosage Forms
Similar to the approach discussed for setting limits for Solid Dosage Forms, the data from the
Antimicrobial Effectiveness Testing could be used to compare to the microbial levels actually
recovered from equipment surfaces during cleaning validation and assess the level of risk and
the criticality of cleaning procedures. For example, if the Antimicrobial Effectiveness Testing
showed a 3 log reduction in the test organisms for a Semi-solid dosage form, then 1000
CFU/mL could be substituted for the starting value in Table 9.2 and the same analysis run using
the batch size and total equipment surface area for the Semi-solid dosage form. Very similar
results would be experienced. This analysis, like the analysis for Oral Solid Dosage Forms,
demonstrates that low levels of microorganisms on Semi-solid Dosage manufacturing
equipment pose little risk to these products.
One aspect of cleaning validation where microorganisms may play an important part is in Hold
Time studies. (17) As part of a cleaning validation program regulators are requiring
manufacturers to perform studies that examine the effects of holding manufacturing
equipment for a period of time before and after cleaning.
This first case is referred to as a “Dirty Hold Time” study. The purpose is to determine if the
holding equipment prior to cleaning has any effect on the cleaning process. For instance,
product residues may adhere to the equipment over time and be more difficult to remove. For
products containing significant amounts of water, this period of time may allow
microorganisms to grow and proliferate. The period of time for these “Dirty Hold Time” studies
is typically determined based on normal operational situations where equipment realistically
may not be cleaned immediately, such as over a long holiday weekend. This is really a challenge
to removing chemical residues and any microorganisms that have grown would be subjected to
the same cleaning conditions described above.
The second case is referred to as a “Clean Hold Time” study. The purpose is to determine if the
holding or storage of equipment after cleaning has any effect on the cleanliness of the
equipment. By regulation, cleaned equipment must be covered to prevent cross contamination
so product residues are probably not a concern in a “Clean Hold Time” study. However, if
equipment is not cleaned properly and allowed to stay wet with water, any microorganisms
present may have an opportunity to proliferate and contaminate the next batch they are used
in. Unlike the situation for “Dirty Hold Time” studies cleaned equipment may not be used for
longer periods of time so these studies may require more careful planning. However, there is
evidence that clean equipment does not continue to accumulate microorganisms over time. One
study showed no increase in bioburden data even over a 2 year period. (18) The data derived
from such studies can be evaluated as described above for Solid and Semi-solid Dosage Forms.
Most microbial testing involves direct surface sampling of the equipment. Typical sampling
equipment includes Sterile Swabs and Rodac plates which require incubation periods of several
days. More recently swabs (see Pocketswab Plus at have become available
that detect the presence of ATP, (Adenosine Triphosphate) and can gives results in 25 seconds
or less. Using these swabs can allow immediate release of cleaned equipment and can provide
an at-line PAT (Process Analytical Technology) tool. For equipment that cannot be reached for
swabbing, such as piping, rinse sampling with sterile buffer solutions can be used. The samples
are then incubated for several days and counts made.
This chapter explored the significance of microbiology in cleaning validation. For the most part
microbiology plays an incidental role in cleaning validation. In general, the level of
microorganisms encountered on pharmaceutical manufacturing equipment pose little risk to
Oral Solid Dosage and Semi-solid Dosage products or the patients using them. It has been
argued that the presence of microorganisms in Solid Dosage Forms can pose a risk for patients
who are immuno-compromised or suffer from cystic fibrosis. (19) This author even remembers
a movement in 1990’s whose proponents were trying to make all non-sterile products sterile.
But in a truly Science and Risk-based world, analysis reveals that these risks are overstated and
other factors such as foods, the environment and/or hospital materials pose a far greater risk
of microbial exposure to patients than that presented by Solid Dosage and Semi-solid Dosage
The author would like to express his gratitude to Stephanie Wilkins, Sneha Deshpande,
Bharatkumar Agrawal and Kailash Rathi for their review of this chapter and helpful suggestions.
1. 21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals.
2. EudraLex - Volume 4, Part I, Chapter 3, Premise and Equipment
3. PIC/S Guide to Good Manufacturing Practice for Medicinal Products Part I, Chapter 3 -
Premises and Equipment.
4. Good Manufacturing Practices for Pharmaceutical Products: Main Principle Annex 4, WHO
Technical Report Series 908, 2003
5. Jimenez, Freddy A. “Enforcement of the Current Good Manufacturing Practices for Solid
Oral Dosage Forms After United States v. Barr Laboratories” Food And Drug Law Journal
Vol. 52
6. Jimenez, Luis, ed. “Microbial Contamination Control in the Pharmaceutical Industry” 2004
Marcel Dekker, Inc.
7. Kushwaha, Poonam, “Microbial Contamination: A Regulatory Perspective” Journal of
Pharmacy Research Vol.3. Issue 1. January 2010
8. “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach”
9. Verghese, George “Aqueous Cleaning and Solvent Substitution in API Manufacturing”,
Pharmaceutical. Technology, Vol. 27, No. 10 (2003)
10. Rohsner, D. and W. Serve “The Composition of Cleaning Agents for the Pharmaceutical
Industries” Pharmaceutical Engineering March/April 1995, Vol. 15 No. 3
11. USP Method <1112> “Microbiological Attributes of Non-sterile Pharmaceutical Products
Application of Water Activity Determination”
12. ICH Topic Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances
13. Docherty, Scott E. “Establishing Microbial Cleaning Limits for Non-Sterile Manufacturing
Equipment” Pharmaceutical Engineering 1999. Vol.19, Iss. 3
14. Orchard, Terry, “Setting Acceptance Criteria from Statistics of the Data” Biopharm
International; Nov 2006; 19, 11.
15. USP Method <51> “Antimicrobial Effectiveness Test”
16. Sutton S. and D. Porter “Development of the Antimicrobial Effectiveness Test as USP
Chapter <51>” PDA Journal of Pharmaceutical Science and Technology Vol. 56, No. 6,
November/December 2002
17. Troy Fugate, “Hold Time Studies: A Lost Parameter for Cleaning Validation” Journal of
Validation Technology; May 2007; 13, 3
18. Forsyth, Richard, Equipment-Hold Time for Cleaning Validation Pharmaceutical
Technology; Cleveland Apr 2008. Vol.32, Iss. 4
19. Martinez, Jose E. “Microbial Bioburden on Oral Solid Dosage Forms” Pharmaceutical
Technology North America. Feb 2002. Vol. 26, Iss. 2
Full-text available
This article will provide a detailed discussion of the science-, risk-, and statistics-based approaches in the American Society for Testing and Material (ASTM) E3106 "Standard Guide for Science Based and Risk Based Cleaning Process Development and Validation".
Full-text available
The microbiological attributes of pharmaceutical ingredients are often critical to final product quality. FDA expects from the manufacturers to measure and characterize the bioburden of their products. The concern of FDA and compendia towods microbial contamination described in this article. This article also describes the source, methods of detection, and methods of elimination of microbial contamination.
This article discusses the introduction of microbial testing as part of the cleaning validation strategy for nonsterile manufacturing. It reviews monitoring tools, setting justifiable limits, protocol modifications, and future challenges.
Solvent substitution and the use of aqueous cleaning for API manufacturing processes has been driven by several factors such as the relatively high cost of solvent acquisition, storage, and disposal; increasing regulatory pressures; the inefficiency and often ineffectiveness of the solvent-based processes; and overall economics. Efficient and successful conversion from solvent-based to aqueous-based cleaning is feasible with appropriate investment in equipment modifications and attention to the details of cleaning process design and validation.
This article shows how Probabillistic Tolerance Intervals of the form. "We are 99% confident that 99% of the measurements will fall within the calculated tolerance limits" can be used to set acceptance limits using production data that are approximately Normally distributed. If the production measurements are concentrations of residual compounds that are present in very low concentrations, it may be appropriate to set acceptance limits by fitting a Poisson or an Exponential Distribution.
Regulatory agencies expect companies to establish and monitor clean equipment- and dirty equipment-hold times for manufacturing equipment as part of their cleaning validation program, if hold times are validated under properly defined and controlled conditions, it is possible that monitoring either or both hold times may not be necessary.
This authoritative reference presents an up-to-date review of the testing methods, emerging technologies, and analytical systems and procedures used to prevent the microbial contamination of pharmaceutical processes, products, and environments. It identifies new tools for sample analysis and evaluation and the impact of these advancements on the continuous supply and manufacturing of pharmaceutical products. With more than 100 tables and 430 current references, the book contains a detailed analysis of microbial contamination recalls for nonsterile and sterile pharmaceutical products, demonstrating the distribution of microorganisms worldwide and the identification by geographical regions. © 2004 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business.
The antimicrobial effectiveness test first appeared as a USP General Chapter in the 18th revision, official September 1, 1970. This chapter, at the beginning, was designed to evaluate the performance of antimicrobials added to inhibit the growth of microorganisms that might be introduced during or subsequent to the manufacturing process. As Good Manufacturing Practices (GMPs) became a governing principal in pharmaceutical manufacturing, the purpose of the test was refined to focus on activity of the preservative system as a protection against inadvertent contamination during storage and usage of the product. This article will review the history of the antimicrobial test; its function, technique, and the background discussions that resulted in the changes from the test that appeared in USP XVIII to that of the current USP 25.
The Composition of Cleaning Agents for the Pharmaceutical Industries" Pharmaceutical Engineering
  • D Rohsner
  • W Serve
Rohsner, D. and W. Serve "The Composition of Cleaning Agents for the Pharmaceutical Industries" Pharmaceutical Engineering March/April 1995, Vol. 15 No. 3
Microbiological Attributes of Non-sterile Pharmaceutical Products – Application of Water Activity Determination
  • Usp Method
USP Method <1112> " Microbiological Attributes of Non-sterile Pharmaceutical Products – Application of Water Activity Determination "