PHARMACEUTICAL PROCESS VALIDATION WHY TO DO, WHEN TO DO AND HOW TO DO IT

Validation has become one of the pharmaceutical industry’s most recognized and discussed subjects. It is a critical success factor in product approval and ongoing commercialization. This article provide brief introduction about the pharmaceutical process validation and its importance according to regulatory provision, also provide the answer of question like why to do, when to do and how to do it. This work is to present an introduction and general overview on process validation of pharmaceutical manufacturing process. Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels. End-product testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end. In pharmaceutical industry, Process Validation performs this task to build the quality into the product because according to ISO 9000:2000, it had proven to be an important tool for quality management of pharmaceuticals.

THE REGULATORY BASIS FOR PROCESS VALIDATION
Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The ultimate legal authority is Section 501(a)(2)(B) of the FD&C Act, which states that a drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or were not operated or administrated in conformity with CGMP. Assurance must be given that the drug would meet the requirements of the act as to safety and would have the identity and strength and meet the quality and purity characteristics that it purported or was represented to possess. That section of the act sets the premise for process validation requirements for both finished pharmaceuticals and active pharmaceutical ingredients, because active pharmaceutical ingredients are also deemed to be drugs under the act.  
The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and 211, were promulgated to enforce the requirements of the act. Although these regulations do not include a definition for process validation, the requirement is implicit in the language of 21 CFR 211.100, which states: “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.”

THE REGULATORY HISTORY OF PROCESS VALIDATION
Although the emphasis on validation began in the late 1970s, the requirement has been around since at least the 1963 CGMP regulations for finished pharmaceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved in 1962 with Section 501(a) (2) (B) as an amendment. Prior to then, CGMP and process validation were not required by law. The FDA had the burden of proving that a drug was adulterated by collecting and analyzing samples. This was a significant regulatory burden and restricted the value of factory inspections of pharmaceutical manufacturers. It took injuries and deaths, mostly involving cross-contamination problems, to convince Congress and the FDA that a revision of the law was needed. The result was the Kefauver–Harris drug amendments, which provided the additional powerful regulatory tool that FDA required to deem a drug product adulterated if the manufacturing process was not acceptable. The first CGMP regulations, based largely on the Pharmaceutical Manufacturers Association’s manufacturing control guidelines, were then published and became effective in 1963. This change allowed FDA to expect a preventative approach rather than a reactive approach to quality control. Section 505(d)(3) is also important in the implementation of process validation requirements because it gives the agency the authority to withhold approval of a new drug application if the “methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity.”
Another requirement of the same amendments was the requirement that FDA must inspect every drug manufacturing establishment at least once every 2 years. At first, FDA did this with great diligence, but after the worst CGMP manufacturing situations had been dealt with and violations of the law became less obvious, FDA eased up its pharmaceutical plant inspection activities and turned its resources to more important problems.
The Drug Product Quality Assurance Program of the 1960s and 1970s involved first conducting a massive sampling and testing program of finished batches of particularly important drugs in terms of clinical significance and dollar volume, then taking legal action against violative batches and inspecting the manufacturers until they were proven to be in compliance. This approach was not entirely satisfactory because samples are not necessarily representative of all batches. Finished product testing for sterility, for example, does not assure that the lot is sterile. Several incidents refocused FDA’s attention to process inspections. The investigation of complaints of clinical failures of several products (including digoxin, digitoxin, prednisolone, and prednisone) by FDA found significant content uniformity problems that were the result of poorly controlled manufacturing processes. Also, two large-volume parenteral manufacturers experienced complaints despite quality control programs and negative sterility testing. Although the cause of the microbiological contamination was never proven, FDA inspections did find deficiencies in the manufacturing process and it became evident that there was no real proof that the products were sterile. What became evident in these cases was that FDA had not looked at the process itself—certainly not the entire process—in its regulatory activities; it was quality control- rather than quality assurance-oriented. The compliance officials were not thinking in terms of process validation. One of the first entries into process validation was a 1974 paper presented by Ted Byers, entitled “Design for Quality”. The term validation was not used, but the paper described an increased attention to adequacy of processes for the production of pharmaceuticals. Another paper—by Bernard Loftus before the Parenteral Drug Association in 1978 entitled “Validation and Stability”—discussed the legal basis for the requirement that processes be validated.
The May 1987 Guideline on General Principles of Process Validation was written for the pharmaceutical, device, and veterinary medicine industries. It has been effective in standardizing the approach by the different parts of the agency and in communicating that approach to manufacturers in each industry.

Contamination Control Under Foot

By Dr. Tim Sandle

Control of airborne and surface microorganisms and airborne particles in a cleanroom is achieved through the physical operation of the heating, ventilation, and air conditioning system and cleaning and disinfection techniques.¹
Even with these factors taken into account, contamination can still occur. One area of concern is the entry of personnel² and the movement of equipment into and out of cleanrooms.³ Traditional ways to control these activities have centered on gowning techniques and the cleaning of equipment. To accomplish this, cleanroom mats are frequently used to remove particles from footwear and from trolley wheels.
Research undertaken at an independent laboratory—and described in this article—evaluates the performance of temporary adhesive mats and semi-permanent polymeric flooring in retaining contamination from footwear, and particle generation from removing layers of the adhesive mats.
The dispersal of particles, including microorganisms, in turbulent flow clean areas occurs relatively easily.⁴ After a period of time, any particles present will be either removed from a clean area through the air-handling system, or will be deposited onto a surface as a result of gravity, convection, or diffusion. Most particles that land on surfaces will eventually become re-suspended into the air and thus represent a contamination concern. One common way in which re-dispersal happens is from people walking across floors.⁵
Cleanroom mats
Special flooring commonly is used at cleanroom entrances to reduce the level of contamination from the transit of materials and people. The flooring is designed to remove a significant level of the particles carried on footwear and equipment. Major risk areas are changing rooms and air locks.⁶
This cleanroom flooring typically is in the form of temporary or semi-permanent mats. Temporary mats are typically adhesive and are commonly called sticky mats. Semi-permanent mats are made of polymeric material.
Adhesive mats consist of layers of plastic film coated with an adhesive and are attached to the floor; the mat is 'sticky' when a foot comes into contact with the surface. The mats are disposable and after a period of use, the top layer is removed from the stack and discarded. The removal of this top layer generates airborne particles that are dislodged from the surface of the mat.
Permanent mats have a polymeric surface manufactured from a material and are deposited onto a non-conductive substrate surface and become bound to the surface through electro-static forces. The mat remains permanently tacky and the flooring is designed to retain any particulate contamination that comes into contact with its surface.
Differences between types of mats
Given the range of adhesive-based, peel-off disposable flooring produced by different companies, it is not surprising that the adhesive capabilities, and hence the ability of the flooring to reduce the number of particles carried on footwear, varies. There have been few published studies into the effectiveness of adhesive cleanroom flooring, despite its long history and widespread use.⁷ For polymeric flooring, studies have shown the effectiveness of the flooring in reducing large numbers of microorganisms.^8-10 However, no major studies looked at the ability of adhesive mats or polymeric flooring to remove particles.
In 2012, a study into the particle retention of mats, and the particle generation from adhesive mats when the top layer is removed, was undertaken at an independent laboratory. The study examined:
• The level of particles captured on a cleanroom mat.
• The level of particles that typically remain on shoes and overshoes after a person stepped onto and then off a cleanroom mat.
• The level of particles released into the air when the top layer from an adhesive mat is removed.
In order to examine these different conditions, six different types of adhesive mats were compared with two pieces of polymeric flooring—one newly fitted piece and one that had been in place for one year.
The study was conducted in an ISO Class 7 cleanroom. To simulate a level of use, 10 different people walked across the mats. Mats were assessed in the clean state (no footsteps on the mat); in the semi-dirty state (10 footsteps on the mats); and in the dirty state (20 footsteps on the mats). For the peeling test, mats were peeled either slowly or rapidly.
The study was carried out for each type of mat and polymeric flooring for people wearing overshoes and for uncovered shoes. Each person took one step. In order to create ‘worst case’ conditions, the steps on the mats and flooring were overstrikes. Particles were assessed using an optical particle counter fitted with a surface sampling probe to measure particles deposited onto the mat surfaces, and with an alternative probe for measuring airborne particulates.
The cumulative particle size examined was the one of most interest for pharmaceutical and healthcare facilities: particle counts of 0.5 µm and larger.
To obtain the different conditions required (slow peel, semi-dirty mats; fast-peel, dirty mats; and so forth), many replicate experiments were required. The cleanroom was given time to “clean up” in between each measurement and the surface particle counter probe was sanitized in between each measurement.
Results from walking across the different mats
For the first part of the study, the level of surface particles remaining on shoes and overshoes was examined before and after personnel had walked across each type of mat. Figure 1 displays the average results of the level of particles from shoes before an individual has walked across a mat and then afterwards. The adhesive mat types are coded 1 to 6. The polymeric flooring, assessed as new flooring and year-old flooring, is abbreviated as ‘polym’.
Figure 1: Surface particle counts from shoes measured before and after walking across a mat.
Click for larger image
Figure 1 indicates that the level of particles on shoes measured before an individual stepped on the mat was reduced after the individual had stepped onto the mat. The graph indicates that a far greater reduction was seen for the  polymeric flooring compared with the six adhesive mats. The adhesive mats reduced the particle level by 20% to  50%; the polymeric flooring reduced levels by approxi-mately 80%.
Figure 2: Surface particle counts from overshoes measured before and after walking across a mat.

Click for larger image.
Figure 2 displays the equivalent mean results of particle levels from overshoes. Figure 2 indicates that the level of particles from the overshoes measured before an individual walked across the mat was reduced after the individual stepped onto the mat. The reduction was ranged from 13% to 45% for the adhesive mats and was approximately 80% for the polymeric flooring.
Figure 3: Surface particle retention by flooring type (uncovered shoes).

Click for larger image.
Surface particle etention
Given the differing levels of particle removal between the adhesive mats and the polymeric flooring, the levels of particles retained by the different flooring types also varied, with the polymeric flooring retaining far greater numbers of particles. This is reflected in Figure 3, (uncovered shoes) and Figure 4 (overshoes).
Figure 4: Surface particle retention by flooring type (overshoes).

Click for larger image
Particle count generation from mat removal
The third part of the study examined the level of particles released from removing the top layer from each adhesive mat. As discussed above, the adhesive mats were studied in clean, semi-dirty, and dirty conditions. The top layer of each tested mat was removed using slow-peel and fast-peel variable speeds. The results are displayed in Figure 5.
Figure 5: Particle generation from mat peeling (0.5 µm).

Click for larger image
Figure 5 shows that the level of particles increases in relation to the degree of dirt on the mat. The clean mat generated fewer particles than the semi-dirty mat; and the semi-dirty mat generated fewer particles than the dirty mat. In addition, the level of particles also rises if the mat is peeled away quickly compared with the mat being peeled away slowly.
Summary
The study of particles and cleanroom flooring revealed that the levels of particles removed from footwear and retained on the flooring were highest for the polymeric flooring when compared with a range of different adhesive mats.
A further risk arises from the use of disposable adhesive cleanroom mats in relation to the removal of the top layer of the mats, as the act of peeling an adhesive mat generates a relatively high number of particles.
The results are general trends and there are different variables to consider. Nevertheless, there appear to be advantages relating to the use of polymeric flooring as a means of ensuring tighter contamination control.
References
1. Sandle T. Cleanroom Cleaning and Disinfection: Eight Steps To Success. Controlled Environments. 2012;March:8-11.
2. Sharp J, Bird A, Brzozowski S, O’Hagan K. Contamination of cleanrooms by people. European Journal of Parenteral and Pharmaceutical Sciences. 2010;15(3):75-81.
3. Clibbon C. An evaluation of the effectiveness of polymeric flooring compared with "peel off" mats to reduce wheel- and foot-borne contamination within cleanroom areas. European Journal of Parenteral Sciences. 2002;7(2):13-15.
4. Prout G. A Comparison of Polymeric Flooring and Disposable Mats in Pharmaceutical Cleanrooms. Pharmaceutical Technology. 2010. Online article: http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=691057 (accessed June 19, 2012).
5. Hambraeus A, Bengtsson S, Laurell G. Bacterial Contamination in a modern operating suite. Journal of Hygiene. 1978;80:169-174.
6. Clibbon C. Polymeric flooring versus peel-off mats. Manufacturing Chemist. 2002;73(9):65-6.
7. Whyte W, Shields T, Wilson IB. Cleanroom mats; an investigation of adhesive strength and soil removal from shoes. Environmental Engineering.1996;9(1):21-29.
8. Ranta LS. An evaluation of polymeric flooring and its effectiveness in controlling airborne particles and microbes. European Journal of Parenteral Sciences. 2002;7(3):79-80.
9. Sandle T. The use of polymeric flooring to reduce contamination in a cleanroom changing area. European Journal of Parenteral and Pharmaceutical Sciences. 2006;11(3):75-80.
10.  Barrett GFC. Polymeric Flooring Demonstrates Particle Retention Properties. CleanRooms. 1996;November.

New Weapon to Fight Falsified Drugs

By Bikash Chatterjee

The European Commission took a big step forward in protecting the interests of ethical drug manufacturers and the safety of the public with its Falsified Medicines Directive 2011/62/EC. There is an important distinction to make: Falsified drugs are not counterfeit drugs, which often contain no active ingredient at all. Rather, falsified drugs may contain substandard ingredients, or active ingredients in the wrong dosage. In some cases, they may be deliberately and fraudulently mislabeled with respect to identity and source, or possess fake packaging.
Released for comment in 2011, the consultation phase for this directive ended in April 2012¹ and a planned adoption of the delegated act will be in force in 2013. The new legislation takes aim at manufacturers of active pharmaceutical ingredients (APIs) that are not compliant with good manufacturing practices (GMPs). The implications of the new directive go beyond API manufacturers and extend ultimate responsibility back to the drug manufacturer for GMP compliance. In addition, the onus is on the drug manufacturer to ensure that the API manufacturer is good distribution practice (GDP)-compliant. In the United States, there are no formal regulatory standards for good distribution practices.
In Europe, however, all manufacturers, distributors, and importers are expected to register with the competent authority of the European Union (EU) member state where they are established. Distributors and importers are responsible for confirming the quality and integrity of the API in the final drug product.
The European Commission further requires the 25 member states to take appropriate measures to ensure that all products within their respective territories comply with this requirement.
A global battlefield
History has no shortage of high profile public health disasters that can be traced to the industry’s newfound commitment to a global supply chain. In 2007, Baxter’s Heparin disaster exposed a number of significant supply chain management problems on the part of the manufacturer and the U.S. Food and Drug Administration (FDA). The post-mortem analysis showed shared culpability on all fronts and highlighted the complexity of doing business in another country.
For example, in 2008, when Baxter sent inspectors to retroactively evaluate its supply chain, they were denied access to upstream workshops and consolidators. The FDA was also denied access to two upstream consolidators of heparin. Further complicating the inspection, the API manufacturer had been classified within China as a chemical plant and therefore was not registered with the Chinese State Food and Drug Administration (sFDA). The FDA was unsuccessful in getting cooperation from Chinese authorities to investigate beyond the API maker.
Such are the realities of attempting to verify and enforce the new API directive. The threat has not been lost on FDA and EU authorities. In a January 2010 warning letter, the FDA claimed that employees at XiAn Libang Pharmaceutical Co. Ltd. were manipulating testing data. The agency informed the API manufacturing plant that it would not consider new marketing applications until the observed violations were sufficiently addressed. In February 2010, Indian manufacturer Glochem was found to have falsified batch-manufacturing records for clopidogrel, an antiplatelet medicine. EU inspectors discovered at least 70 batch-manufacturing records in the plant’s waste yard. All the records had been re-written, and in some cases, original entries had been changed. In 2008, the FDA cited Indian manufacturer Ranbaxy Laboratories Ltd. for a number of U.S. GMP violations, including alleged falsification of stability testing records.²
Up to now, quality auditors have evaluated API manufacturers against the requirements defined in Eudralex Vol. 4, Part II (ICH Q7A, titled Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients). The Falsified Medicines Directive 2011/62/EC seeks to extend the scope of the existing EU GMP directive (2003/94/EC) to include APIs. In effect, this would make no difference between the quality requirements for a drug substance (API) and its final drug product.
One could argue that this has been coming for some time. In 2011, the FDA started citing API manufacturers that could not meet the Stage 1 requirements of the new process validation guidance.
Similarly, the EU directive has raised the bar in terms of accountability, and opened the door to enforcement. Unlike a drug product, which can be verified by a regional authority, a drug substance must be verified by a Qualified Person (QP). The EU is extending this requirement as a prerequisite to marketing authorization, requiring a QP declaration of compliance prior to approval.
Marching orders
For drug manufacturers, the requirements for adopting an outsourcing plan have just become a lot more complex. Outsourcing strategies must begin to integrate the requirements of the drug substance manufacturer within the quality management system. Defining touch points that extend upstream to the pre-approval inspection (PAI) manufacturers’ suppliers and sub-suppliers, and downstream to the API intermediate and regulatory starting material should generate demonstrable evidence of compliance with ICH Q7A and the EU GMP Directive 2003/94/EC to obtain a QP declaration.
Even if it has no such requirement, the United States may be able to leverage the enforcement muscle of the EU to reduce the risk of importing falsified material. For final drug manufacturers, the barriers to outsourcing continue to rise. It remains to be seen if China, where a major portion of all APIs imported to the United States are currently manufactured, will support this new directive and allow greater transparency in the matter of qualifying manufacturers and suppliers.
References
1. Jenteges B, et al. EU Directive to Thwart Noncompliant APIs, PDA Letter, April 2012.
2. The Pew Health Group. After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs. July 2011.

Putting Cleaning Protocols to the Test

By John Broad, Barbara Kanegsberg

As indicated in a related article in this issue of Controlled Environments,¹ cleaning validation of reusable medical devices is undergoing re-evaluation and updating. The Association for the Advancement of Medical Instrumentation (AAMI) TIR30:2011² lists methods that have been developed by several countries to test the efficacy of cleaning of a variety of reusable medical devices. This technical information report (TIR) also includes testing methods for the detection of soil proteins, fats, carbohydrates, endotoxins, and viable microorganisms. These tests can be used to provide data to support verification that the manufacturer’s recommended cleaning procedure using a selected cleaning agent is effective for a particular device.
Because cleaning endpoints are not defined in AAMI TIR 30:2011, a major challenge faced by instrument manufacturers is determining how clean is clean. However, based on references provided in the compendium, a level for each of five markers, specifically protein, carbohydrate, hemoglobin, endotoxin, and bacterial spore reduction, can be determined (Table 1). These can be used as reasonable reference points.
Recent studies have determined the efficacy of cleaning processes for an assortment of reusable medical devices. The case studies summarized below provide examples of a supportable approach to demonstrate the effectiveness of a manual cleaning process of surgical instruments.
The purpose of the studies was to assess the efficacy of sponsor-proposed cleaning protocols (i.e., cleaning protocols proposed by manufacturers of reusable medical devices) based on the level of residual soil marker.

Table 1: Soil markers used in evaluating efficacy of cleaning.

Device Category	Soil Marker	Reference
Critical Orthopedic	Whole blood, serum, milk powder, and saline	[2]
Semi-Critical Rectal and Esophageal	Peanut butter, evaporated milk, butter, flour, lard, dehydrated egg yolk, saline, printer’s ink, blood, Huckers artificial soil (fecal equivalent)	[3]

Study design, test methodology
The study, conducted at NAMSA laboratories, included critical and semi-critical devices; the devices under consideration were tested using soils that emulate biological soils that are appropriate for cleaning efficacy studies (Table 1). The cleaning procedure developed was based on the type of contamination expected on the device, design features, and the potential for the patient to come in contact with pathogens. For example, the appropriate test soils for verifying cleanliness of devices that enter the sterile body cavity (Table 2, Devices A and C through J) are different than those for devices that contact the mucosa and/or intact skin (Table 2, Device B).
The evaluations were conducted per a NAMSA protocol that is based on AAMI TIR30:2011 and AAMI TIR12:2010.³

Methods
Cleaning: Three soiled devices of each type were subjected to the sponsor-proposed cleaning procedure immediately after soiling. Each device was cleaned using freshly prepared cleaning solutions for a total of three or five cycles, depending on the device type. One common positive control (soiled but not cleaned) and one common negative control (not soiled and not cleaned) was included for each device type. After cleaning, each device was visually inspected for remaining soil. The volume and temperature of the cleaning solutions and rinse water were reported. While all device manufacturers specified the use of an enzymatic cleaner, the cleaning agent and process used was specific to the device manufacturer. Enzymatic solutions were prepared using manufacturers’ instructions for device soaking and then again for device sonication. The temperature of the cleaning solution was recorded prior to use.
Manual cleaning processes might employ sponges, soft bristle brushes, and/or pipe cleaners. Cleaning action might include wiping, scrubbing, and/or flushing depending on the protocol put forth by the device manufacturer. Mechanical cleaning utilized a commercial washer/disinfector.

Table 2. Protein and hemoglobin results of the analysis.

Test Article Device Category	Cleaning Method	Benchmark (average)Protein Level(µg/cm2)	Test Article Device Protein Level(µg/cm2)	Benchmark (average)Hemoglobin Level(µg/cm2)	Test Article Device Hemoglobin Level(µg/cm2)
A	Semi-Critical/ Manual	6.4	< 0.48	2.2	1.9
B	Semi-Critical/ Manual	6.4	0.67	2.2	1.7
C	Critical/ Manual	6.4	1.5	2.2	3.6
D	Critical/ Manual	6.4	2	2.2	< 2.1
E	Critical/ Manual	6.4	0.52	2.2	< 1.9
F	Critical/ Mechanical	6.4	0.72	2.2	<2 .1=".1" td="td">
G	Critical/ Manual	6.4	0.55	2.2	<2 .1=".1" td="td">
H	Critical /Manual	6 .4	0.5	2.2	< 2.0
I	Critical/ Manual	6.4	< 0.50	2.2	< 2.0
J	Critical/ Manual	6.4	< 0.49	2.2	< 2.0

Device Extraction: For each device type, three test devices, one positive control, and one negative control were extracted individually in bags filled with 12 mL of USP grade 0.9% sodium chloride (NaCl). Devices were extracted using 20 minutes of sonication followed by agitation by hand for 30 seconds.  After each extraction, the solution was thoroughly mixed and decanted. The extraction procedure was repeated an additional two times (for a total of three extractions) using fresh solvent. The extracts were used for protein and hemoglobin analysis. Running tap water was used to rinse the devices for a period of three minutes prior to and after sonication. The volume of the rinse water ranged from 3,400 to 3,510 mL and the temperature of the rinse water ranged from 36 to 37 C.
Protein Analysis: A Pierce kit was utilized.⁴ A 150 μL aliquot of the 200 μg/mL, 20 μg/mL and 2.5 μg/mL bovine serum albumin (BSA) standards, the test extracts, and the blank solution were placed in individual wells in a 96-well plate; 150 μL of working reagent was added to each well. The plate was gently agitated by hand and incubated at 37 C for two hours. The plate was removed from the incubator and allowed to cool to room temperature. The plate was analyzed by a UV-visible spectrometer at 562 nm. The absorbance of the standards and test extracts were corrected for the blank solution absorbance; and a standard curve was generated to determine the protein concentration of the extracts.
Hemoglobin Analysis: An ASTM Method was utilized.5 A 2.0 mL aliquot of 10^-3 M copper (II)-phthalocyanine complex solution and 2 mL of pH 2.0 buffer solution were placed in separate test tubes. A 5 mL aliquot of test extracts, hemoglobin standards, or a 0.9% NaCl control was added to each test tube and mixed. A 250 µL aliquot from each test tube was added to a 96-well plate. Using an eight-channel micropipette, 50 µL of 0.2 M solution of potassium peroxymonosulfate was added to each well to start the reaction. Since the reaction is time dependent, solutions were plated in rows of eight with the first four wells containing the hemoglobin standards and control, followed by test extracts.
After 0.2 M solution of potassium peroxymonosulfate was added to the last row in the plate, the plate sat at room temperature for 25 minutes.
The plate was then analyzed by a UV-visible spectrometer at 603 nm. Absorbance of the standards and test extracts were corrected for respective control absorbance and a standard curve was generated from each row on the plate to determine the hemoglobin concentration of the extracts.
Conversion: Units of µg/mL were converted to µg/cm² by multiplying times the volume of extraction fluid used for each device (mL) and dividing by the device surface area (cm²).
No debris was observed during inspection of the cleaned devices. Results are summarized in Table 2, page 21.
Discussion
As indicated, on a review of published data2 for various types of reusable devices, after device cleaning, the average levels of the two soil markers under consideration were:
• Protein: < 6.4 µg/cm²
• Hemoglobin: < 2.2 µg/cm²
As additional studies are performed and more data becomes available, these benchmark levels will become more definitive.
In all but one instance, the proposed cleaning methods evaluated utilizing protein and hemoglobin analysis met the acceptance criteria (the benchmark, average level).
Device C exceeded the average residue level for hemoglobin. It should be noted that the device in question is of a fairly complex design and would present greater inherent cleaning challenges. The method of cleaning was revised and the repeat testing (product G) showed a marked improvement.
Each device manufacturer must set testing and acceptance criteria that are appropriate to the configuration, materials of construction, and end-use requirements of each specific device under consideration. The rationale for testing and the rationale for acceptance criteria must be carefully considered and documented for the device in question.
References
1. Kanegsberg B, Kanegsberg E, Broad J. Update: Guidance for Cleaning Validation of Reusable Medical Devices, Controlled Environments. 2012:July/August;34-35.
2. AAMI TIR30:2011. A compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices.
3. AAMI TIR12:2010.  Designing, testing, and labeling reusable medical devices for reprocessing in health care facilities: A guide for medical device manufacturers.
4. Pierce Micro BCA Protein Assay Kit (Thermo Scientific).
5. ASTM F 756-08:2008. Standard Practice for Assessment of Hemolytic Properties of Materials.

Going Retro

By Richard Bilodeau, PE

Q: My decade-old facility has never been commissioned and I'm suspecting some operations, energy, and cost issues are lurking. Can you guide me through a retro-commissioning process?
A: The old saying, "What you don't know will kill you" applies perfectly to managing existing facilities. Clean manufacturing facilities with their additional layers of complicated building and process systems magnify that truth.
Buildings and their systems are designed to perform to specified standards. However, as time marches on, this performance degrades or systems are modified, and many times those modifications aren't documented. The result: Building performance declines, energy usage increases, and the operations budget takes a wasteful hit.
A previous column, "Building Commissioning: Real or Smoke & Mirrors?" (Controlled Environments, May 2011) examined the commissioning process. This column will examine the unique considerations of commissioning an existing facility.
The term "retro-commissioning" commonly is used to refer to the commission of an existing building that has not previously been commissioned. Retro-commissioning is one scope of Existing Building Commissioning (EBCx). The Building Commissioning Association (BCA) defines Existing Building Commissioning as: "… a systematic process for investigating, analyzing, and optimizing the performance of building systems through the identification and implementation of low/no cost and capital-intensive Facility Improvement Measures and ensuring their continued performance. The goal of EBCx is to make building systems perform interactively to meet the Current Facility Requirements (CFR) and provide the tools to support the continuous improvement of system performance over time. The term EBCx is intended to be a comprehensive term defining a process that encompasses the more narrowly focused process variations such as retro-commissioning, re-commissioning, and ongoing commissioning that are commonly used in the industry."
Retro-commissioning is typically driven by three objectives: reducing energy use with resultant operational savings, safety/security, and the comfort of the building's occupants. These objectives fall under the main goal of commissioning: to verify and document that the facility systems function as the original design intended. Manufacturing facilities—and particularly clean manufacturing facilities—introduce another layer of complexity to any retro-commissioning undertaking, given their complex process utilities to consume vast amounts of energy. Historically, commissioning was developed with a strong focus on building HVAC systems.
In their Best Practices in Commissioning Existing Buildings guide, the BCA outlines the purpose of existing building commissioning as to:
• Verify that a facility and its systems meet the CFR
• Improve building performance by saving energy and reducing operational costs
• Identify and resolve building system operation, control, and maintenance problems
• Reduce or eliminate occupant complaints and increase tenant satisfaction
• Improve indoor environmental comfort and quality and reduce associated liability
• Document system operation
• Identify the operations and maintenance (O&M) personnel training needs and provide such training
• Minimize operational risk and increase asset value
• Extend equipment life-cycle
• Ensure the persistence of improvements over the building's life
• Assist in achieving LEED for existing buildings
• Improve the building's Energy Star rating
Regardless of purpose, goals, objectives and systems complexity, the payback against investment can be fast and significant, in terms of operations costs (both saved and avoided) and energy consumption, as well as increased productivity driven by improved employee comfort and health. While the payback period for a retro-commissioning investment is influenced by the age and complexity of the building and its systems, building size, manufacturing system and process complexity, as well as the scope of investigation and remediation, the basic retro-commissioning process remains the same.
Retro-commissioning also provides facilities managers with an ongoing building maintenance toolbox filled with baseline system performance data, defined performance criteria, and the structure through which to continuously track, evaluate and adjust systems performance. This is important, as commissioning should not be considered a one-off effort. To maximize its benefits, commissioning should be viewed as an iterative and ongoing process. Facilities engineers should consider re-commissioning their buildings every 3 to 5 years.
Because retro-commissioning is an ongoing process and drives superior operations and maintenance practices, it's important to ensure that all key stakeholders understand the process and benefits of EBCx and are vested in the process.
A facility's senior management, operations and maintenance departments, key manufacturing engineering personnel, and any equipment vendors with ongoing relationships to a facility should be on board. It is often advantageous to have representatives of key occupancy groups participate, or at the very least, they should stay informed about the progress. An EBCx consultant should be an independent, certified CxA professional, not someone working for a current contractor or equipment supplier—and not a member of the facility's operations and maintenance staff. The commissioning agent should function as an independent expert and as an owner's advocate.
How do you structure a retro-commissioning project? Again, the BCA offers some advice for phases and goals in its Best Practices guide:
• Planning: Develop the EBCx goals, facility requirements, and a commissioning plan
• Investigation: Conduct field inspections, gather data, test, and analyze to assess system performance and identify improvement opportunities
• Implementation: Complete the desired facility improvements, and verify the results and performance
• Turnover: Conduct a systematic transition from a commissioning activity and the commissioning team to standard operating practice and the operations and maintenance team
• Persistence: Implement systems and tools to support both the persistence of benefits and continuous performance improvement over time.
Investment in staff training during the turnover phase is critical to success. Once the opportunities for improved performance are identified and rectified, it is very important to ensure that the operations and maintenance staff is thoroughly trained. Failing to do so puts the investment in retro-commissioning at risk. Videotape training sessions so new staff members can be easily brought up to speed.
Ensuring that the buildings are operating as intended, while optimizing energy and operations cost efficiencies, are core requirements that link a facility engineer's efforts to a company's business success.

Cleanroom Trash or Recycled Treasure?

By Albe Zakes, Global VP, Media Relations, TerraCycle, Trenton, N.J.

Both environmental habits and cost-cutting measures are becoming commonplace in facilities across the United States, including cleanrooms and research laboratories. Due to the nature of work performed and the hazardous chemicals, pathogens, and dust that may be present, companies have often found themselves with large amounts of waste. Reducing the amount of material used in the cleanroom or laboratory is the best way to cut back on waste, but may not be possible at all times. However, recycling programs can greatly diminish the amount of used material sent to the landfill.
Research—as well as partnerships between distributors, suppliers, waste haulers, and other businesses—have provided controlled environment facilities the opportunity to cut costs, produce less waste, and reduce their impact on the environment. For example, Kimberly Clark Professional (Roswell, Ga.) and TerraCycle (Trenton, N.J.) have launched a business-to-business recycling program for cleanroom garments and  other waste.
Many cleanroom garments are made from spunbond polypropylene bonded to polyolefin film laminate. These materials are not traditionally recyclable because they cannot be processed by municipal facilities. Despite a lack of local processors, the materials are readily recyclable and can be melted down for reuse. A cleanroom with 100 operators can eliminate approximately 25 tons of waste in one year by recycling used materials.
By recycling instead of sending the garments to the landfill, 14 grams of carbon emissions can be saved per item, according to an independent lifecycle analysis performed by Zerofootprint, a Toronto- and New York-based organization that tracks environmental statistics. The carbon emissions are saved because the existing material can be made into recycled plastic, replacing the need for manufacturers to make virgin plastic.
Disposal options
The most common disposal option for garments—as well as other non-hazardous cleanroom facility waste—is the landfill. Some programs collect, launder, and resell garments, giving extra life to the garments. Eventually, the garments wear out and are sent to a landfill.  Another option is incineration or waste-to-energy. This option is better than landfill disposal because the incineration process can help produce electricity, will not litter the planet, overfill landfills, or potentially contaminate groundwater.
However, with incineration, greenhouse gases are released into the atmosphere. Additionally, incineration can cause odors in the surrounding area and eliminate the possibility of a second life for the waste.
Recycling to raw materials
In the recycling process for cleanroom garments, a facility signs up and receives shipping boxes and labels to send the used garments to a collection facility. A barcode tracks participation and waste reduction for recycling statistics and analysis.
Currently, Kimberly Clark’s KIMTECH Pure* A5 apparel and KleenGuard A10-A65 product families are recycled, including accessories such as hoods, boot covers, and sleeves that are made with polypropylene fabric. More materials are being tested, and the number of accepted items is expected to grow.
After collection, the items are palletized and shipped to a TerraCycle waste facility where boxes are checked into inventory. The garments are shipped to a processor for shredding. The non-plastic elements, including zippers, elastic, and paper labels, are separated and reused.
The plastic is sent to an extrusion pelletization process, where it is heated and melted, then formed into small plastic pellets, which are molded or extruded into new products. The pellets also can be mixed with other recycled materials and molded into plastic lumber, watering cans, bike racks, picnic tables, or other products.
Other recycling improvements
Aside from garments, cleanrooms also produce waste from sterile gloves, hand towels, wipers, and other non polypropylene-based materials. The only current disposal methods for these and bio-hazardous material are incineration or decontamination and reuse. Kimberly Clark Professional and TerraCycle plan to expand their recycling program in 2012 to include more waste streams from cleanrooms and make the programs easier for smaller facilities that cannot accommodate shipments that are large enough to palletize.
In 2011, the companies launched a pilot program for the collection of disposable nitrile gloves at Life Technologies Corp.'s Pleasanton, Calif. facility. With the addition of the glove recycling, the landfill diversion rate of the facility increased from 37% to 83%, demonstrating the critical sustainable differences that a program can enable in a cleanroom or laboratory setting. The numbers are also indicative of the difference that potentially could be made in hospitals, manufacturing locations, and other facilities that use disposable gloves at a high rate and have no other recycling solution.
The environmental implications for cleanroom garment recycling are not fully understood because the program has been available for less than a year. As cleanrooms continue to recycle, they can divert tons of waste from the landfill every year. For every coverall recycled, a half-pound of waste does not go to a landfill. When facilities across the country participate, the number can add up.
In the first six months of the garment recycling program, participating cleanrooms and laboratories sent in more than 7,000 pounds of garment waste and requested more than 1,000 pallets of collection boxes to return additional garments. Collections are on track to surpass 350,000 pounds in coming months, a positive indication of how much cleanroom waste can be diverted from the landfill.
Sustainability measures can often be costly and time-consuming, but companies are paying attention to these drawbacks and trying to make programs accessible and affordable. In the end, the time, effort, and cost could lead to financial and environmental savings.
By getting a start on recycling efforts, cleanrooms and laboratories can make an investment in good practices and be prepared for potential emissions, waste output, and impact reduction regulations in the future.

Ask the Facilities Guy: Site Selection for Clean Manufacturing Facilities

By Richard Bilodeau, PE

Question: I expect to be involved in either selecting a site for new construction or a building for renovation in order to expand our manufacturing operations. Can you give me some advice?
Answer: Locating a new clean manufacturing facility requires unique considerations in the manufacturing world. While supply chain, end customer geographies, logistics, labor force and financial incentives are some of the major drivers, the facilities engineer is becoming an increasingly important player on the site location team.
Let’s step back and take a quick overview of just a few of the high level factors driving facility location decisions, before we drill down to specifics more directly aligned with facilities engineers.
SOME C-SUITE CONSIDERATIONS:
Financial incentives: As the saying goes, “it’s all about the money.” Communities, states, and countries are playing hardball on the economic development field, devising complex economic development and tax incentive programs to score coveted manufacturing jobs. And the jobs that are part of the clean manufacturing sector are a prize catch. The competition hasn’t been regional for a long time, it’s global. This has forced localities to become more sophisticated and aggressive in their offerings. Companies are looking for—and getting— comprehensive packages that include not only a wide variety of longer term tax incentives, but also infrastructure improvements, training programs, expedited regulatory approvals, and other concessions. Maryland recently made news with its $100 million tax incentive program, designed to stimulate knowledge based economic development, including biotech and nanotech investments. The state anticipates it will attract an additional $70 million in VC funding.
Educational resources: Technology based companies evolve quickly and their employees need to be able to procure the education they need to stay ahead of the curve. Tech companies also rely increasingly on partnerships with educational institutions, in areas such as R+D, new product development, and spinning out new businesses. There’s a reason the most vibrant technology clusters co-locate where the most hallowed halls of higher education reside.
Available and qualified labor force: Today’s clean manufacturing jobs require a well educated and flexible workforce. Generally even today’s entry level positions require a higher competency in math and science than in the past. And while automation has reduced the total number of employees historically required on the production line, they need to be more technically savvy.
Predictable future: Investing in a new clean manufacturing plant is a significant—and ideally long term—investment. Stability and predictability on political, regulatory, and economic fronts—including tax rates, incentive programs, and training opportunities—are important to taking home the gold.
Global market: Where are key and growing markets located and where are they expected to be located in the future? What impact does shipping have on costs?
THE ROLE OF THE FACILITIES PROFESSIONAL:
At the end of the day, the facilities professional is responsible for bringing a greenfield or renovated facility online, overseeing the design and engineering, regulatory permitting, construction, tool installation, qualifications, ramp-up, operations and, over the longer term, changes in process and product lines, as well as maintenance. Ultimately, you’ll “own” the facility, so due diligence when selecting a site or building for renovation is a wise investment.
Project definition: As odd as it may sound, it can be amazing to watch companies skip developing a thorough project definition, scope, and schedule before taking another step. The facilities engineer is an important part of that effort. If you haven’t been included, knock on some doors and state your case. Progressive companies view their facilities engineer as a strategic thinker, not a short order cook serving up a brick and mortar menu.
Part of the project definition includes the business case for the new or renovated expansion. The business case informs not only the “go/no go” decision, but the scope. Are you looking to increase yields? Can that be accomplished by retooling within an existing footprint? Is it possible to outsource the manufacture of some product lines in order to make room for higher margin products where you want in-house manufacturing control? Is the objective to increase sales, provide for new product lines, or accommodate future growth?
Consultant team: Carefully construct your expert team—based on anticipated project parameters. It’s your lifeline to success. Invest up front to ensure your company has the expertise required. A few items to consider:

• How will you handle the site or property search? Commercial realtors, economic development officials, government agencies, internal personnel?
• Will you manage the project or look to a turn-key developer?
• Greenfield construction or renovate an existing building?
• Own or lease?
• Located domestically or offshore?
• Are the proposed sites or candidate buildings for renovation environmentally “clean”?
• Custom build or modular cleanrooms?
• What facility characteristics are driven by the company’s defined manufacturing processes and the likelihood of shifting process requirements in the near term?
• How will you handle energy engineering? LEED certified, registered, or simply built to LEED standards (or not)?
• How about regulatory permitting, construction delivery method, or process engineering? Tool hook-up?

Make sure you have experts onboard to advise you or handle these issues—and more.
Your consultant team is best structured when it also includes experts internal to your organization, especially those who understand your manufacturing processes and operations. Don’t forget logistics, finance, legal, communications, and government affairs.
Build a team capable of anticipating any contingency. As issues arise through the life of the project, you aren’t caught needing to bring new players up-to-speed.
CHECKLIST
When looking at candidate sites or existing buildings, keep these primary considerations in mind:

• Adequacy of roadway infrastructure: This is no time to select a site where “You can’t get there from here” as the old saying goes. Make sure the surrounding road system can handle both the quantity and types of traffic you anticipate, whether generated by employees, suppliers, or shippers. This article assumes you’ve already selected the general geographic location based on sound business analysis.
• Utilities: Electricity, water, sewer. Cleanrooms can place a heavy demand on utilities. Are the utilities adequate, or can they economically be brought up to par?
• Prior contamination of site, soils and existing buildings: Make sure you have a certified “clean” site, undertake responsible due diligence to take your company out of the CERCLA liability chain.
• Wetlands and other environmentally sensitive habitats or site features: Woe is the day when an endangered species is discovered on site when you’re already committed.
• Soils, ledge, topography: Can the site physically and economically support the development footprint, with room for future expansion?
• All those zoning and other regulations requiring compliance: Spend the time sorting it all out.
• Existing buildings: During this economic downturn, a lot of “bargain buildings” are available for sale. Run through the items listed above when analyzing existing real estate. Then add a few more items to the list: Asbestos? PCBs? Lead paint? Underground storage tanks? Universal and hazardous wastes? This is no time to be “penny wise and pound foolish.”
• Make sure existing buildings can support your operations and future growth plans. Is the roof able to support the required mechanical systems? Are you erroneously assuming the building can be expanded up, sideways or down? Will the cost of renovation exceed the cost to build new? Consider the “opportunity costs” if the organization is required to compromise operationally.

It’s an uncertain world out there. Bringing your expertise—and the collective knowledge of a well constructed team—to bear on developing new or renovated facilities will go a long way to ensuring success.