Solids …….Liquids

The differences in the cleaning of equipment utilized for solid and liquid formulations are
quite significant. The distinction between these formulation types is related to how
contamination might be left on the equipment and dispersed in subsequent products.

Liquid formulations may have greater ability to penetrate equipment seals and joints, hindering their
removal. In contrast, solid formulations may have unique abilities to form aggregations of
product. This "clumping" may inhibit "wetting" by cleaning agents thereby limiting the ability to "rinse" the residual product away.
The "distribution" of the contaminant is often considered to be quite different for solid and
liquid formulations as well. Liquid products are often considered to have superior dispersion
of active ingredients uniformly across surfaces, while solid products are expected to have
more point to point variability, based primarily upon equipment configuration.

Formulation Attributes

Attributes of the formulation have been identified in the section on residues to have a great influence on the ability to clean.

In general, solid and liquid formulations represent the range
of physical product attributes and soluble and insoluble represent the ability of products within the continuum to react with the agents which are used to clean.

Non-Sterile -Sterile

The Production of sterile formulations increases the extent of cleaning operations relative to non-sterile products. Sterile manufacturing facilities must control microbial, endotoxin and particulate levels to a degree not common with non-sterile products.

Not only are the number of concerns increased but the nature of these contaminants makes the successful removal of
these items (and their validation) more difficult.

Sampling methods for these contaminant are more subjective, the analytical methods more demanding, and the validation generally
more difficult to complete.

Concerns relative to microbial and particulate control are lessened in the production of nonsterile products but are still important.

Practices which minimize the potential for contamination by "objectionable organisms" are common in the manufacture of non-sterile formulations such as oral liquids and topical products.

Highly Characterized - Poorly Characterized

 

In addition to the myriad of cleaning processes which must be evaluated, there are additional
difficulties: appropriate limits for active agents must be selected; this limit might be based
upon a not yet identified therapeutic dose.

Alternatively, using the lowest dose, or considering using the worst case might save time on scale up, provided that the appropriate
assays for these levels have been developed and validated.

Other difficulties include the requirement that appropriate analytical methods must be developed for all formulations.
Clearly, while the validation of cleaning is a difficult task in a production facility, the
unknowns inherent in clinical product manufacturing, where the product is poorly
characterized, make the task even more challenging.

Other areas where products may be poorly characterized include bioprocesses and syntheses
where vast numbers of related molecules may be formed, in addition to the primary product.
While there are generally requirements that all of these potential "contaminants" developed
during the manufacturing process be identified, these materials may not be characterized well
enough to have specific, low-level assays developed for each of them.

The establishment of appropriate limits for each of these substances is equally complicated and may not be feasible.

PDA-TECH - Highly Characterized -Poorly Characterized

 

logo

Highly Characterized -Poorly Characterized
The introduction of pre-approval inspection requirements for NDA and ANDA approval has resulted in greater scrutiny being placed on documentation describing the development of the formulation.

Regulatory agency expectations for cleaning validation are formidable within
the confines of marketed product manufacturing (typically highly characterized products) but
placing the same requirements upon developmental drugs (typically poorly characterized)
makes cleaning validation even more difficult.

During product development, the formulation process and equipment to be utilized in production are evaluated in order to ensure a consistent process for commercial scale manufacture.

Before the final equipment selections
are made, however, a wide variety of equipment combinations may be tried, resulting in a vast
array of cleaning combinations.

PDA FILE LINKS

PDA

Low Risk - High Risk Drugs

Many firms have used dedicated facilities and/or equipment, or conducted cleaning verification in order to circumvent some of the inherent difficulties in processing high risk drugs.

The difficulties of reproducibly demonstrating successful cleaning may make it operationally easier to dedicate the equipment and/or facility to the production of a single product rather than attempt to clean to the necessary level of cleanliness.

The route of administration of a product may affect the level at which the product is found to be allergenic, toxic or potent.

Generally speaking, injectable products, intra-ocular
formulations, and some inhalants which provide direct access to the systemic circulation systems of patients are a much greater concern in terms of cross-contamination.

PDA TECHNICAL LITERATURE

 

Low Risk - High Risk Drugs
1.The residual limits utilized for cleaning validation are often closely related to the allergenicity/toxicity/potency of the materials in question.

2.The limits are eased when the materials being removed are generally of lower pharmacological activity.

3. At the other extreme, there are numerous materials and formulations, where even minute quantities can
have pharmacological activity.

4. The equipment and the procedures utilized to clean the
equipment might be identical, yet the production of materials with known adverse effects may require that tighter limits be achieved.

.5.Cleaning, sampling and analytical methods may need
to be refined to a high degree of sensitivity to ensure that the equipment has been properly cleaned.

PDA CLEANING VALIDATION

Product Atttibutes

1.The cleaning of equipment is closely tied to the type of materials being removed from the surface.
2.The product formulation is often the key in establishing appropriate cleaning acceptance criteria, challenge methods and sampling techniques.

INTRODUCTION TO GOOD MANUFACTURING PRACTICE

Materials of Construction

1.The materials of construction of the equipment should be considered carefully when
establishing a cleaning validation program.

2. The attributes of the surface to be cleaned will define the residue to surface interactions, identify possible contaminants and point to areas
which may not be readily cleaned or accurately sampled.

3.The CGMPs (211.65) state that,
"a) Equipment shall be constructed so that surfaces which contact components, inprocess
materials, or drug products shall not be reactive, additive or absorptive so as
to alter the safety, identity, strength, quality or purity of the drug product beyond
official or other established requirements.
"b) Any substances required for operation, such as lubricants or coolants, shall not come
into contact with components, drug product containers, closures in-process materials,
or drug products so as to alter the safety, identity strength, quality or purity of the
drug product beyond official or other established requirements."

4.Equipment should not be reactive, additive or adsorptive with the process materials which
contact them.

5.The use of porous surfaces for multiple products should be avoided (filters,
filter bags, fluid bed drier bags, membrane filters, ultra filters).

6.Any surfaces which have these properties will require review during cleaning validation evaluations to ensure adequate
product removal and minimize the potential for cross-contamination.

7.The interaction of cleaning agents with surfaces that are likely to display these properties (e.g., seals, gaskets,
valves) should be assessed.

Minor Equipment - Major Equipment

 

1.The distinction between "major" and "minor" equipment is not a definitive one.

2. The CGMPs make mention (211.105) of "major" equipment, but are silent on the subject of "minor"
equipment except with regard to items described as utensils (211.67).

3.Despite this failure within the CGMPs, it is necessary to identify those pieces of equipment (major) which are
central to the production process and those pieces of equipment (minor) which perform a
secondary role.

4.Typically the cleaning of "major" equipment will be the subject of individual, highly specific
SOPs. In contrast, "minor" equipment and "utensils" are often cleaned using broadly defined
procedures which describe the methods to be used in general terms.

Non-Critical Site -- Critical Site

 

1.Critical sites are those locations in which a contaminant is in danger of affecting a single dose
with a high level of contamination.

2. Critical sites often require special cleaning emphasis.

3. It may be appropriate to establish more intensive sampling schedules for critical sites, set tighter
acceptance criteria for critical sites and ensure that enough detail is included in cleaning
procedures to provide for reproducible cleaning of critical sites.

Non-Product Contact -- Product Contact Surfaces

 

1.Traditionally, the validation of cleaning has focused on product contact surfaces.

2. Programs for the elimination of cross-contamination must address non-product contact surfaces if they
are to be truly effective.

3.In practice, cleaning validation requirements may change with nonproduct
contact surfaces in accordance with the less critical nature of these areas.

4.When establishing the requirements for non-product contact surfaces, it is important to review the
possible interactions of that area with the process.

Dedicated - Non-Dedicated Cleaning Equipment

1.The issues of dedicated and non-dedicated equipment can also arise when considering the
equipment used for cleaning.

2.CIP systems, for example, are frequently used for many different tanks in a single facility.

3.Inherently, the design of CIP systems should preclude cross-contamination through appropriate valving and back-flow prevention.

4..Care should be taken with shared devices which apply cleaning agents, such as spray balls or spray nozzles
which, themselves, may require cleaning.

5.Certainly any recirculation within the CIP system should be configured carefully during system design and monitored closely during routine
operation.

6.COP equipment, such as an ultrasonic sink, may also be used for multiple equipment loads.

7.With cleaning apparatus such as the sink, the removal of potential contaminants from the sink,
itself is a concern.

8. Sinks and washers frequently use recirculation systems to economically
remove residuals from surfaces without undue waste.

8.The cleanliness of the re-circulated materials should be evaluated during cleaning validation to ensure that contaminants are not
being re deposited on the equipment to be cleaned.

Dedicated - Non-Dedicated Manufacturing Equipment

1.Dedicated equipment is used solely for the production of a single product or product line.
Concerns over cross-contamination with other products are markedly reduced.

2.Dedicated equipment must be clearly identified with the restrictions of use in order to prevent potential
errors during cleaning and preparation.

3.Where the same piece of equipment is utilized for a range of product formulations, (i.e., non dedicated
equipment), the prevention of cross-contamination between products becomes the
main objective in the cleaning validation effort.

4.Clearly, cleaning non-dedicated equipment represents a more significant obstacle to overcome.

A GMP HUB - ENRICH YOURSELF: Equipment Characteristics / Materials of Construct...

A GMP HUB - ENRICH YOURSELF: Equipment Characteristics / Materials of Construct...: 1. Equipment usage during production is another important aspect to consider in establishing a cleaning validation program. 2.It is import...

Equipment Characteristics / Materials of Construction

1. Equipment usage during production is another important aspect to consider in establishing a cleaning
validation program.

2.It is important to understand not only the range of products that are likely to
come into contact with the various equipment surfaces, but also the role that the equipment plays in
the production train.

3.This will help to establish the contamination and cross-contamination potentials
of the equipment.
4.Equipment design characteristics, as established during product development, are often driven by
equipment functionality and the requirements of the process.

5.With the current emphasis on cleaning validation, it makes sense that "cleanability" be a key criterion in the design of equipment.

CIP vs COP

Clean-In-Place (CIP)	Clean-Out-of-Place (COP)
The cleaning of large pieces of equipment may be performed in the equipment's permanent location, generally in a configuration very similar to that in which it is utilized for production.	Smaller equipment items are frequently transported to a designated cleaning or wash area where the cleaning procedure is performed.
easy to handle	transferring of item may lead to cross contamination
automated or manual method adopted	automated or manual method adopted

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Cleaning Program Criteria

Automated Cleaning	Manual Cleaning
Automated cleaning will usually provide reproducible results.	Manual cleaning is a universal practice within the pharmaceutical industry
Process control is inherent in automated systems and process monitoring is frequently integral with the control system	There are many pieces of equipment and portions thereof for which construction and/or configuration make manual cleaning a necessity.
The validation of an automated system requires that the cycle is proven to be rugged and will provide reproducible results under a given range of operating conditions.	The control of manual cleaning is accomplished by operator training, well defined cleaning procedures, visual examination of equipment after use and prior to the next use, and well-defined change control programs.
Control system validation is a large part of the validation of an automated cleaning system.	It may be desirable to identify worst case cleaning situations (in terms of operator experience and/or cleaning methodology) for validation purposes.
	With manual cleaning, concern must also be given to the ruggedness of the method. Successful reproducibility is a function of strict adherence to written procedure

 

 

 

Continues

Cleaning Program Criteria

When establishing a cleaning validation program, it is important to first characterize the types of
cleaning that are used in the facility.

The cleaning methods that are used in a facility can reveal
important factors with regard to process control, process reproducibility, the best ways in which to
challenge the process, the best ways in which to collect samples and the best ways in which to
monitor cleaning effectiveness during routine cleaning.

Continues

Use of the Cleaning Continuum

Table 1: The Cleaning Continuum
Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Automated Cleaning
Clean-out-of-Place (COP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clean-in-Place (CIP)
Dedicated Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Dedicated Equipment
Product Contact Surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Product Contact Surfaces
Non-Critical Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Critical Site
Minor Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major Equipment
Low Risk Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High Risk Drugs
Highly Characterized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poorly Characterized
Sterile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Sterile
Solid Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid Formulations
Soluble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insoluble
Single Product Facility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Product Facility
Campaigned Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Campaigned Production
Simple Equipment Train . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complex Equipment Train

Continues

Use of the Cleaning Continuum

Use of the Cleaning Continuum

 

1.The cleaning continuum provides some of the primary points to consider in any cleaning validation
program.

2. The continuum helps firms to establish the parameters which are critical factors for
individual products, thereby enabling them to set priorities, develop grouping philosophies and
establish the "scientific rationale" which will govern the cleaning program.

3.The continuum will assist in determining which processes, equipment and products represent the greatest concerns and may
help to establish the criticality of cleaning limits and methods.

4.The continuum should be used during
the initial phases of defining a cleaning validation program or during new product development.

 

 

Continues

PDA CLEANING VALIDATION–CLEANING CONTINUUM

2.1 Use of the Cleaning Continuum
The intent of this section is to describe the limits of the cleaning continuum (see Table 1).

These limits represent the extremes in the range of operating differences found within the industry which
preclude a uniform approach.

At each end of the continuum, the cleaning validation requisites are
either simple or complex.

Recognition that there are many of these coupled limits, and that each
cleaning process has a unique place within each level of the continuum, explains why specific
industry-wide approaches have been so difficult to develop.

 

………..continues

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REGULATORY LINKS

Useful links

References that can be viewed or downloaded will have a blue link in their title. When you click on the link the document will appear in a new window, or you will be redirected to an external website where the reference may be viewed or purchased.
Reference Categories: Regulatory Guidance, Validation Strategies, Economics and Return on Investment, Applications and Methods, RMM Technologies, Quality and General Overviews and Books.

Regulatory Guidance

2012. EMA. Questions and Answers on Post Approval Change Management Protocols. Committee for Medicinal Products for Human Use (CHMP). European Medicines Agency. EMA/CHMP/CVMP/QWP/586330/2010.
2012. Federal Register. Food and Drug Administration. Amendments to Sterility Test Requirements for Biological Products Final Rule . 21 CFR Parts 600, 610, and 680 [Docket No. FDA–2011–N–0080]. 77(86): 26162-26175.
2012. Miller, M.J. Rapid Micro Methods and EMA’s Post Approval Change Management Protocol. European Pharmaceutical Review. 17(2): 65-67.
2011. Riley, B. A Regulators View of Rapid Microbiology Methods. European Pharmaceutical Review. 16(5): 59-61.
2011. Food and Drug Administration. Advancing Regulatory Science at FDA. A Strategic Plan. U.S. Department of Health and Human Services, Rockville, Maryland.
2011. Federal Register. Food and Drug Administration. Amendments to Sterility Test Requirements for Biological Products. Proposed Rule. 21 CFR Parts 600, 610, and 680 [Docket No. FDA–2011–N–0080]. 76(119): 36019-36027.
2010. Miller, M.J. Microbiology Series. Article 4: The Implementation of Rapid Microbiological Methods (EMA Perspectives). European Pharmaceutical Review. 15(4): 17-19.
2010. Miller, M.J. Microbiology Series. Article 3: The Implementation of Rapid Microbiological Methods (FDA Perspectives). European Pharmaceutical Review. 15(3): 18-21.
2010. EMA. Post-Authorisation Procedural Advice Human Medicinal Products. Committee for Human Medicinal Products (CHMP). European Medicines Agency. EMEA-H-19984/03 Rev 16.
2009. ICH. Q8: Pharmaceutical Development. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline, Q8 (R2), Current Step 4 version.
2008. ICH. Q10: Pharmaceutical Quality System. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline, Q10, Current Step 4 version.
2008. Food and Drug Administration. Draft Guidance for Industry. Validation of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular and Gene Therapy Products. U.S. Department of Health and Human Services, Rockville, Maryland.
2008. European Commission. EU guidelines to good manufacturing practice, Annex 1. Manufacture of sterile medicinal products. EudraLex, European Union: Brusselles, Belgium.
2008. Moldenhauer, J. A case for regulatory guidelines for verifying automated microbiological methods. American Pharmaceutical Review. 11(5): 36-43.
2005. ICH. Q9: Quality Risk Management. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline, Q9, Current Step 4 version.
2005. EMA. Quality of medicines Q&A: Part 2. Water - Microbiological Control of Water. Joint CHMP/CVMP Quality Working Party, European Medicines Agency.
2005. Miller, M.J. Rapid Microbiological Methods and FDA's Initiatives for Process Analytical Technology and Pharmaceutical cGMPs for the 21st Century: A Risk Based-Approach. American Pharmaceutical Review. 8(1): 104-107.
2005. Moldenhauer, J. Rapid microbiological methods and the PAT initiative. BioPharm International.
2004. Food and Drug Administration. Final report for pharmaceutical cGMPs for the 21st Century - A risk-based approach. U.S. Department of Health and Human Services, Rockville, Maryland.
2004. Food and Drug Administration. Guidance for industry: PAT - A framework for innovative pharmaceutical development, manufacturing, and quality assurance. U.S. Department of Health and Human Services, Rockville, Maryland.
2004. Food and Drug Administration. Guidance for industry: Sterile drug products produced by aseptic processing -Current good manufacturing practice. U.S. Department of Health and Human Services, Rockville, Maryland.
2003. Food and Drug Administration. Guidance for industry: Comparability Protocols - Protein Drug Products and Biological Products, Chemistry, Manufacturing, and Controls Information. U.S. Department of Health and Human Services, Rockville, Maryland.

Validation Strategies

2010. Miller, M.J. Microbiology Series. Article 2: The Implementation of Rapid Microbiological Methods (Validation Strategies). European Pharmaceutical Review. 15(2): 24-26.
2010. Duguid, J. Top Ten Validation Considerations When Implementing a Rapid Mycoplasma Test. American Pharmaceutical Review. 13(4): 26-31.
2010. Miller, M.J. Developing a validation strategy for rapid microbiological methods. American Pharmaceutical Review. 13(3): 28-33.
2010. Miller, M.J.; Moldenhauer, J. Revision of Technical Report #33. American Pharmaceutical Review. 13(1): 86-91.
2009. USP 32-NF27. General Information Chapter <1223>, Validation of alternative microbiological methods. U.S. Pharmacopeial Convention, Rockville, Maryland.
2009. European Pharmacopoeia 6.4. Informational chapter 5.1.6. Alternative methods for control of microbiological quality. European Directorate for the Quality of Medicines (EDQM), Strasbourg, France.
2008. Newby, P. Implementation, validation and registration of rapid microbiological methods. European Pharmaceutical Review. 13(3): 67-73.
2007. Green, S. Industry strategy case study E: How to select, validate, and implement a rapid microbiology method and get it approved - A true story. American Pharmaceutical Review. 10(5): 102-107.
2005. Sutton, S. Validation of Alternative Microbiology Methods for Product Testing: Quantitative and Qualitative Assays. Pharmaceutical Technology. 29(4): 118-122.
2005. Newby, P. Implementation, validation and registration. European Pharmaceutical Review. 10(2): 92-95.
2004. Newby, P.J. Implementation, validation and registration of rapid microbiological methods. American Pharmaceutical Review. 7(4): 10-15.
2000. PDA. Technical Report #33. Evaluation, Validation and Implementation of New Microbiological Testing Methods. PDA Journal of Pharmaceutical Science and Technology. Supplement 54(3). Parenteral Drug Association, Bethesda, Maryland.

Economics and Return on Investment

2009. Miller, M.J. Breaking the rapid microbiological method financial barrier: A case study in RMM return on investment and economic justification. BioPharm International. 22(9): 44-53.
2009. Miller, M.J. Rapid microbiological methods and demonstrating a return on investment: It's easier than you think! American Pharmaceutical Review. 12(5): 42-47.
2009. Gadal, P.; Yvon, P. Rapid Microbio ROI - Calculating scientific benefits as return on investment dollars. Pharmaceutical Formulation & Quality. 11(3): 44-47.
2009. Miller, M.J. Ensuring ROI from your RMM. Pharmaceutical Manufacturing. 8(6): 32-35.
2009. Miller, M.J. Quality Risk Management and the Economics of Implementing Rapid Microbiological Methods. European Pharmaceutical Review. 2: 66-73.
2006. Ghandi, M. Efficiency with Rapid Microbiology Methods. American Pharmaceutical Review. 9(5): 16-19.

Applications and Methods

2012. Ragheb, S.M.; Yassin, A.S.; Amin, M.A. The Application of Uniplex, Duplex, and Multiplex PCR for the Absence of Specified Microorganism Testing of Pharmaceutical Excipients and Drug Products. PDA Journal of Pharmaceutical Science and Technology. 66(4): 307-317.
2012. Jimenez, L.; Rana, N.; Amalraj, J.; Walker, K.; Travers, K. Validation of the BacT/ALERT 3D System for Rapid Sterility Testing of Biopharmaceutical Samples. PDA Journal of Pharmaceutical Science and Technology. 66(1): 38.54.
2011. Miller, M.J. QbD, PAT, and the Future of Microbiology. Environmental monitoring with RMM. Contract Pharma. 13(4): 70-73.
2011. Jimenez, L. Molecular Applications to Pharmaceutical Processes and Cleanroom Environments. PDA Journal of Pharmaceutical Science and Technology. 65(3): 242-253.
2011. Gray, J.C.; Morandell, D.; Gapp, G.; Le Goff, N.; Neuhaus, G.; Staerk, A. Identification of Micro-Organisms after Milliflex Rapid Detection—A Possibility To Identify Nonsterile Findings in the Milliflex Rapid Sterility Test. PDA Journal of Pharmaceutical Science and Technology. 65(1): 42-54.
2011. Gordon, O.; Gray, J.C.; Anders, H.J.; Staerk, A.; Schlaefli, O.; Neuhaus, G. Overview of Rapid Microbiological Methods Evaluated, validated and Implemented for Microbiological Quality Control. European Pharmaceutical Review. 16(2): 9-13.
2010. Sampath, R., Blyn, L.B.; Ecker, D.J. Rapid Molecular Assays for Microbial Contaminant Monitoring in the Bioprocess Industry. PDA Journal of Pharmaceutical Science and Technology. 64(5): 458-464.
2010. Gray, J.C.; Staerk, A.; Berchtold, M.; Mercier, M.; Neuhaus, G.; Wirth, A. Introduction of a Rapid Microbiological Method as an Alternative to the Pharmacopoeial Method for the Sterility Test. American Pharmaceutical Review. 13(6): 88-94.
2010. McIver, D. Using RMM for Environmental Monitoring. Pharmaceutical Manufacturing. 9(7): 37-38.
2010. Gray, J.C.; Staerk, A.; Berchtold, M.; Hecker, W.; Neuhaus, G.; Wirth, A. Growth-promoting Properties of Different Solid Nutrient Media Evaluated with Stressed and Unstressed Micro-organisms: Prestudy for the Validation of a Rapid Sterility Test. PDA Journal of Pharmaceutical Science and Technology. 64(3): 249-263.
2010. Denoya, C.; Sessions, D.; Shabushnig, J. A Rapid Microbiological Assay to Monitor the Effectiveness of a Vaccine Injector Sanitization Following a Microbial Challenge Procedure. American Pharmaceutical Review. 13(4): 54-61.
2009. Williams , K.L. The BET as a Backdrop for Establishing PAT and RMM Goals. American Pharmaceutical Review. 12(7): 42-47.
2009. Duguid, J.; Kielpinski, G.; Seymour, B.; du Moulin, G. Risk Assessment for a Rapid Mycoplasma Test Optimized for Cell Therapy Products. American Pharmaceutical Review. 12(6): 100-104.
2009. Bagur, E. Concurrent Evaluation of both Compendial and Rapid Methods (ATP Bioluminescence) for Monitoring Water Quality in Pharmaceutical Manufacturing. European Pharmaceutical Review. 14(3): 58-68.
2008. Gressett, G.; Vanhaecke, E.; Moldenhauer, J. Why and how to implement a rapid sterility test. PDA Journal of Pharmaceutical Science and Technology. 62(6): 429-444.
2007. McDaniel, A. Microbial Detection in Mammalian Cell Culture Systems. American Pharmaceutical Review, 10(1): 24-29.
2007. Anders, H-J.; Keller, M.; berchtold, M.; Hecker, W. Polyphasic approach to microbial identification. American Pharmaceutical Review. 10(6): 46-52.
2006. Moldenhauer, J. Viability-based rapid microbiological methods for sterility testing and the need for identification of contamination. PDA Journal of Pharmaceutical Science and Technology. 60(2): 81-88.

RMM Technologies

2012. Miller, M.J. Case Study of a New Growth-Based Rapid Microbiological Method (RMM) that Detects the Presence of Specific Organisms and Provides an Estimation of Viable Cell Count. American Pharmaceutical Review. 15(2): 18-25.
2011. Miller, M.J. Detection of Microorganisms Using Micro-Electro-Mechanical Systems (MEMS). European Pharmaceutical Review. 16(6): 7-10.
2011. Miller, M.J. Detection of Microorganisms Using Nucleic Acid and Gene Amplification-Based Rapid Method Technologies. European Pharmaceutical Review. 16(5): 62-65.
2011. Miller, M.J. Detection of Microorganisms Using Optical Spectroscopy-Based Rapid Method Technologies. European Pharmaceutical Review. 16(4): 40-42.
2011. Miller, M.J. Detection of Microorganisms Using Cellular Component-Based Rapid Method Technologies. European Pharmaceutical Review. 16(3): 8-10.
2011. Moldenhauer, J. Proteotypic identification methods - A change in identification methods. American Pharmaceutical Review. 14(3): 34-37.
2011. Miller, M.J. Direct Detection of Microorganisms Using Viability-Based Technologies. European Pharmaceutical Review. 16(2): 14-15.
2011. Miller, M.J. Rapid Microbiological Methods 2011 (A Review of Growth-based Technologies). European Pharmaceutical Review. 16(1): 38-41.
2010. Sampath, R.; Blyn, L.B.; Ecker, D.J. Rapid Molecular Assays for Microbial Contaminant Monitoring in the Bioprocess Industry. PDA Journal of Pharmaceutical Science and Technology. 64(5): 458-464.
2010. Smith, R.; Von Tress, M.; Tubb, C.; Vanhaecke, E. Evaluation of the ScanRDI as a Rapid Alternative to the Pharmacopoeial Sterility Test Method: Comparison of the Limits of Detection. PDA Journal of Pharmaceutical Science and Technology. 64(4): 356-363.
2010. Jimenez, L.; Rana, N.; Travers, K.; Tolomanoska, V.; Walker, K. Evaluation of the Endosafe® Portable Testing System™ for the Rapid Analysis of Biopharmaceutical Samples. PDA Journal of Pharmaceutical Science and Technology. 64(3): 211-221.
2010. London, R.; Schwedock, J.; Sage, A.; Valley, H.; Meadows. J.; Waddinton, M.; Straus, D. An automated system for rapid non-destructive enumeration of growing microbes. PLoS ONE. 5(1): e8609.
2009. Miller, M.J. Evaluation of the BioVigilant IMD-A, a novel optical spectroscopy technology for the continuous and real-time environmental monitoring of viable and nonviable particles, in Environmental Monitoring, Volume 3. Edited by Jeanne Moldenhauer, PDA and Davis Healthcare International Publishing. 269-288.
2009. Miller, M.J. Real-time environmental monitoring: PAT solutions using rapid microbiological methods. European Pharmaceutical Review. 14(4): 40-46.
2009. Miller, M.J.; Lindsay, H.; Valverde-Ventura, R.; O'Connor, M.J. Evaluation of the BioVigilant IMD-A, a novel optical spectroscopy technology for the continuous and real-time environmental monitoring of viable and nonviable particles. Part I: Review of the technology and comparative studies with conventional methods. PDA Journal of Pharmaceutical Science and Technology 63(3): 244-257.
2009. Miller, M.J.; Walsh, M.R.; Shrake, J.L.; Dukes, R.E.; Hill, D.B. Evaluation of the BioVigilant IMD-A, a novel optical spectroscopy technology for the continuous and real-time environmental monitoring of viable and nonviable particles. Part II: Case studies in environmental monitoring during aseptic filling, intervention assessments and glove integrity testing in manufacturing isolators. PDA Journal of Pharmaceutical Science and Technology 63(3): 258-282.
2009. Denoya, C.D. Nucleic acid amplification-based rapid microbiological methods: Are these technologies ready for deployment in the pharmaceutical industry? American Pharmaceutical Review. 12(4).
2002. Costanzo, S.; Borazjani, R.; McCormick, P. Validation of the Scan RDI for routine microbiological analysis of process water. PDA Journal of Pharmaceutical Science and Technology. 56(4): 206-219.
1999. Wallner, G.; Tillmann, D.; Haberer, K. Evaluation of the ChemScan system for rapid microbiological analysis of pharmaceutical water. PDA Journal of Pharmaceutical Science and Technology. 53(2): 70-74.

Quality and General Overviews

2012. Miller, M.J. Framework for Fast Microbiological Assessment. Pharmaceutical Manufacturing. 12(3): 39-41.
2012. Miller, M.J. Rapid Micro Methods: New Year, Old Challenges! European Pharmaceutical Review. 17(1): 8-11.
2011. Pan, Y. Challenges and Strategies for the Application of Rapid Microbiological Methods in the Pharmaceutical Industry . European Pharmaceutical Review. 16(5): 66-69.
2011. Duguid, J.; Balkovic, E.; du Moulin, G.C. Rapid Microbiological Methods. Where Are They Now? American Pharmaceutical Review. 14(7): 18-25.
2010. Verdonk, G.P.H.T. ; Willemse, M.J.; Hoefs, S.G.G.; Cremers, G.; van den Heuvel, E.R. The Most Probable Limit of Detection (MPL) for Rapid Microbiological Methods.. J. Microbiological Methods. 82(3): 193-197.
2010. Miller, M.J. The Implementation of Rapid Microbiological Methods, in Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices. Edited by Madhu Raju Saghee, Tim Sandle and Edward C. Tidswell. Business Horizons.
2010. Miller, M.J. Microbiology Series. Article 6: The Implementation of Rapid Microbiological Methods (Rapid Methods at the PDA Global Conference on Pharmaceutical Microbiology). European Pharmaceutical Review. 15(6): 27-31.
2010. Miller, M.J. Microbiology Series. Article 5: The Implementation of Rapid Microbiological Methods (Highlights of Published Papers). European Pharmaceutical Review. 15(5): 9-11.
2010. Moldenhauer, J. Use of a Viability Test Method. Does It Mean What You Think? American Pharmaceutical Review. 13(5): 22-29.
2010. Miller, M.J. Microbiology Series. Article 1: The Implementation of Rapid Microbiological Methods (Overview of RMMs). European Pharmaceutical Review. 15(1): 39-41.
2009. Miller, M.J. It's Time to Get Rapid! PDA Letter. 45(4): 1-21.
2009. Miller, M.J. Rapid Microbiological Methods in Support of Aseptic Processing, in Practical Aseptic Processing: Fill and Finish. Edited by Jack Lysfjord, PDA and Davis Healthcare International Publishing.
2008. Green, S. Microbiology/Microbiologists - Where next? American Pharmaceutical Review. 11(3).
2008. Dalmaso, G. Product real time release for the microbial critical quality attribute using QbD approach. American Pharmaceutical Review. 11(2).
2008. Fleming, W.H. Rapid Microbiology - What is truly possible? American Pharmaceutical Review. 11(7): 34-40.
2008. Middleton, A. Cutting edge technologies and their potential role in pharmaceutical microbiology. American Pharmaceutical Review. 11(1): 58-65.
2008. Miller, M.J. Rapid Microbiological Methods, in Microbiology in Pharmaceutical Manufacturing, 2nd Edition. Edited by Richard Prince, PDA and Davis Healthcare International Publishing.
2007. Johnson R.A. A "PAT" on the back for Rapid Microbiological Methods. European Pharmaceutical Review. 12(4): 84-88.
2007. Newby, P. The significance and detection of VBNC microorganisms. American Pharmaceutical Review. 10(4).
2007. Mach, C.J.; Ball, P.R.; Arbizzani, L. The Advent of Rapid Microbiological Methods: Background, Applications, and Validation . Controlled Environments.
2007. Fung, D.Y.C. Rapid methods and automation in microbiology in pharmaceutical samples. American Pharmaceutical Review. 10(2): 82-86.
2007. Middleton, A. Rapid microbiological methods: Are the needs of the pharmaceutical industry really being met? American Pharmaceutical Review. 10(5): 108-113.
2006. Hussong, D.; Mello, R. Alternative Microbiology Methods and Pharmaceutical Quality Control. American Pharmaceutical Review. 9(1): 62-69.
2006. Miller, M.J. Rapid Microbiological Methods for a New Generation. Pharmaceutical Manufacturing. 2006; 5(2): 14-23.
2006. Cundell, A.M. Opportunities for Rapid Microbial Methods. American Pharmaceutical Review. 9(7): 50-56.
2006. Cundell, A.M. Opportunities for Rapid Microbial Methods. European Pharmaceutical Review. 1: 64-70.
2006. Denoya, C.D.; Colgan, S.T.; du Moulin, G.C. Alternative microbiological methods in the pharmaceutical industry: The need for a new microbiology curriculum. American Pharmaceutical Review. 9(6).
2006. Cundell, T. Top Five Challenges Facing Pharmaceutical Microbiologists. American Pharmaceutical Review. 9(4): 30-34.
2004. Riley, B.S. Rapid Microbiology Methods in the Pharmaceutical Industry. American Pharmaceutical Review. 7(2): 28-31.
2004. Newby, P.; Dalmaso, G.; Lonardi, S.; Riley, B.; Cooney, P.; Tyndall, K. The Introduction of Qualitative Rapid Microbiological Methods for Drug-Product Testing. Pharmaceutical Technology. Process Analytical Technology. 6-12.

Books

2012. Encyclopedia of Rapid Microbiological Methods, Volume 4. Edited by Michael J. Miller. PDA and Davis Healthcare International Publishing.
2005. Encyclopedia of Rapid Microbiological Methods, Volumes 1-3. Edited by Michael J. Miller. PDA and Davis Healthcare International Publishing.
2003. Rapid Microbiological Methods in the Pharmaceutical Industry. Edited by Martin C. Easter. CRC Press.

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PDA TECHNICAL LITERATURE CLEANING CONTINUUM

A GMP HUB - ENRICH YOURSELF: PDA CLEANING VALIDATION REPORT

A GMP HUB - ENRICH YOURSELF: PDA CLEANING VALIDATION REPORT: Scope The manufacture of modern pharmaceuticals is a complex process involving highly technical personnel, complex equipment, sophisticat...

PDA TECHNICAL LITERATURE CLEANING VALIDATION -SCOPE

The validation programs described herein assume that an overall validation program with appropriate controls is already in place for the facility, utilities, equipment and processes. 

The cleaning of theenvironment is not specifically covered, however many of the same concerns that are considered for
the cleaning of process equipment also impact the cleaning of the environment. 
The monitoring ofmicrobiological and endotoxin contamination and steps for their elimination are mentioned in several sections and should be part of the cleaning validation program.
However this document is notintended to be a comprehensive treatise on microbiological control, or endotoxin limitation.
Other documents have addressed microbiological programs and methods for the environmental monitoring which can be applied to cleaning.

PDA CLEANING VALIDATION REPORT

Scope

The manufacture of modern pharmaceuticals is a complex process involving highly technical
personnel, complex equipment, sophisticated facilities and complicated processes. Individuals
responsible for all aspects of the production, approval and validation of products, such as quality
control, quality assurance, engineering, validation, production, research and development, contractors
and vendors and regulatory affairs personnel may use this document as a resource for establishing or
reviewing the cleaning programs within their facilities.

PDA TECHNICAL LITERATURE TECHNICAL REPORT 29 CLEANING VALIDATION

Scope

This paper applies to biopharmaceutical, bulk pharmaceutical and finished dosage form operations;
liquid, dry, solid and semi-solid dosage forms are covered in both sterile and non-sterile presentations.
Both clinical and marketed product cleaning validation programs are identified

PDA TECHNICAL LITERATURE 29 Points to consider

1.2 Purpose

The purpose of this publication is to identify and discuss the many factors involved in the design,
validation, implementation and control of cleaning programs for the pharmaceutical industry.
The document does not attempt to interpret CGMPs but provides guidance for establishing a cleaning  validation program. 


It identifies the many factors to be considered for all segments of the
pharmaceutical industry. It also identifies specific points to be considered by dosage form
manufacturers, manufacturers of clinical trial materials (CTMs) and manufacturers of bulk
pharmaceutical chemicals and biochemicals. The report covers the different approaches which may be appropriate for the different stages of product development from the early research stages to the commercially marketed product.

STERILE FILTRATION TECHNIQUE

PDA CLEANING VALIDATION

 

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