Wednesday, January 9, 2008

Cleaning in the pharmaceutical industry-past, present, and future

Sir Isaac Newton once wrote that we all "stand on the shoulders" of those many people who came before us. One of those people was Ken Chapman. Ken was a man short in stature, but a giant in his profession and a true gentleman. I still remember the first time I met Ken when I was a young man eager to learn and attending a meeting in Washington in 1981 where FDA top officials were "laying it on the line" in terms of giving their expectations for computer validation.

In those days, it was very clear who were the regulators and who were the regulated. At that time, validation was still in its infancy and we argued incessantly over the terminology, definitions, and the ever increasing list of acronyms. Ken was working at Pfizer and was also on the program. I can still remember how well he argued his points with the FDA speakers. Ken was always kind in his rebuttal, but never backed down from his position. He didn't so much argue as he explored the issues in a way that was always respectful of the other speakers. I think that is why he was so effective.

When you spoke with Ken, you always knew that he heard every single word you said. He gave you the feeling that he had the utmost respect for you and your point of view and was truly interested in what you had to say. Although he could have been a masterful politician, he truly enjoyed his position in the pharmaceutical industry. To Ken, it was not work, but rather his hobby that he got paid for pursuing.

Ken always remembered my name and went out of his way to say hello and ask how my family was. He would always greet me and say "What's new in cleaning validation, Bill?" With Ken, these weren't just idle words--he really wanted to know. He was truly a kind person and will be greatly missed by all of us who knew and loved him, as well as by an industry that will be forever indebted to him. As colleagues, friends, and beneficiaries of his contributions to industry; we all know that Ken Chapman was a class act.

THE ANCIENT DARK AGES OF CLEANING--BEFORE GMP REGULATIONS

Prior to the issuance of the Good Manufacturing Practice (GMP) Regulations in 978 (Reference 1), cleaning was mostly an "orphan" responsibility, meaning it as not considered very important. It was often relegated to the last activity of the day and sometimes performed on third shift. It was usually assigned to the newest employees, i.e., those with the least experience. In addition, the procedures were often very brief, ambiguous, and very much open to different interpretations. In fact, the procedures were often one sentence, "Clean with hot soapy water."

The cleaning agent often was not specified and it was usually perfectly acceptable and understood that ordinary tap water would be used. Most companies cleaned to a "visually clean" standard that was certainly not defined quantitatively. In most cases, a second person did not verify the cleaning. The documentation of the cleaning was not generally recognized as of critical importance. If the equipment was discovered to be insufficiently clean in the light of the next day, then it was simply recleaned--no big deal and no investigation. It was certainly not a widespread practice to determine the consistency of the cleaning process, i.e., process capability studies were not generally performed.

In all probability, there were significant amounts of cross contamination of one product into another since multiple products were manufactured in the same equipment. Facilities were used that were not designed to be readily cleanable. For example, drop ceilings of cellulose type materials were often used that were not "water friendly" and therefore not regularly cleaned since they were considered as non-product contact in nature. Many of the older facilities had not been designed using good engineering practices such as dust control, anterooms, and adequate principles of operator protection. Many of the piping systems had low spots and "deadlegs" that were virtually impossible to clean. Air flow was not controlled and was often insufficiently filtered to remove micron-sized particles.

Many companies had not developed analytical methods sufficiently sensitive to detect the relatively small amounts of cross contamination that we now know can be medically significant. Most sterile products were manufactured using terminal sterilization whereby any microbial contamination could be controlled and eliminated in the final step of the manufacturing process. The use of barrier isolators in laboratory testing had not matured; therefore, there were false positive micro tests that caused considerable additional confusion.

Looking back at that time period, one might conclude that we had some serious issues in light of today's standards. However, it should be stated that many companies probably did a decent job of cleaning. There were no regulations which required the scientific proof of the adequacy of the cleaning. Therefore, since the proof was absent, the worst case assumption must be made that the equipment was not adequately cleaned.

THE IMPACT OF GMP REGULATIONS AND FDA GUIDELINES

One might assume that with the issuance of the Good Manufacturing Regulations in 1978, the Food and Drug Administration (FDA) drew the "line in the sand" and that cleaning improved dramatically and immediately. Unfortunately, this did not happen. The regulations proved to be somewhat interpretative and many companies were not at all sure what they were being required to do. Many considered that the requirements were unfair and too restrictive and that full compliance would be costly.

This "resistance to change" led to the situation whereby regulatory inspectors and investigators would cite a company for deficiencies in their cleaning program only to find that the deficiencies had not been corrected by the time of the subsequent inspections. During the years immediately after the issuance of the GMP regulations, most of the citations were DD Form 483 citations, meaning that the company did not have a deadline by which the issues must be addressed and corrected. Problems were noted, but the manufacturing and cleaning procedures were not immediately changed and products were continuing to be manufactured and released to the market.

In defense of the companies, the work involved in validating or proving the adequacy of the cleaning procedures was potentially staggering. Many of the product release assays were "wet chemistry" methods and were not sensitive enough to determine the trace amounts of residues remaining on equipment. Many companies "did the math" and found that tens of thousands of samples might be required because of the hundreds of products coupled with the numerous individual pieces of equipment involved in the manufacture and packaging of a pharmaceutical product. There needed to be some clarification or explanation of how this huge problem could be addressed.

Eventually, FDA became very impatient and took two very proactive steps to hasten the improvement of cleaning in the industry. First, they issued a guidance document in 1993 entitled, "Guide to Inspection of Validation of Cleaning Processes" (Reference 2). Although intended to serve as guidance for inspectors and investigators, this document spelled out for both regulatory and industry the regulatory expectations for cleaning procedures, cleaning approaches, setting of limits, and validation of the cleaning processes.

By this time the number of citations issued for cleaning was beginning to grow in an exponential fashion. Also, the FDA increased the serious nature of cleaning program deficiencies by issuing Warning Letters to many, many companies. The Warning Letter is much more serious than a 483 violation and contains language such as, "Your products are considered misbranded and adulterated." Another important aspect of the Warning Letter is that the company is required to respond with an indicated corrective action in not more than 15 working days.

These events caused cleaning to suddenly become a premiere issue for the industry. FDA, in effect, threw down the gauntlet and said "We consider cleaning a critical process and if you don't have validated cleaning processes, then the worst case assumption will prevail, namely that your cleaning program is inadequate and your products are contaminated." At about the same time, FDA took Barr Labs to court (U.S. versus Barr Labs,) in an historic trial. Although there were many issues in this case, the judge ruled that Barr must not only identify the cleaning agents used in their cleaning procedures, but must also validate or prove that the cleaning agent itself was removed by the final rinsing, that is: that cleaning validation studies must also be performed for the cleaning agent(s) used in the cleaning procedure since this could also represent a possible contaminant of pharmaceutical products.

THE EVOLUTION OF CLEANING FROM ART TO SCIENCE

Because of the events described in the previous section, cleaning began an evolution from an "art" activity to one based not only upon science but upon good science. Whereas many of the older cleaning procedures were not really subjected to the recognized principles involved in cleaning, a new generation of cleaning procedures began to emerge that had been through the same development process as the pharmaceutical products themselves. Cleaning processes were no longer an "afterthought" or some aspect that could be developed later, but rather an "FDA hot button" that should be considered from the very beginning of the product development cycle. Creative thought was put into the cleaning process to determine what makes a residue difficult to remove from equipment and the roles of solubility, solvent, mechanical action, flow rates, temperature, contact time, and many other variables in the removal process. In essence, the scientific principles of the cleaning process began to be more fully explored and understood.

There were also many other positive activities that occurred. Suppliers of cleaning agents began to "partner" with pharmaceutical companies in developing optimal cleaning agents and procedures that were product specific. Companies embarked on truly understanding the adequacy or inadequacy of their current cleaning procedures by means of the validation process. There were many surprises during this investigative process. Some cleaning procedures were inadequate or inconsistent and were revised, often extensively. There were many important, peripheral issues that came to light. For example, cleaning agents were previously often ordered, received as used directly by production units without Quality Assurance (QA) approval. This practice of exposing product-contact manufacturing and packaging equipment surfaces to non-formulation ingredients without QA approval or Quality Control (QC) testing needed to be stopped. Cleaning had to be integrated into the quality systems approach. For example, cleaning procedures needed to be reproducibly performed and placed under change control whereby changes could not be made to a procedure once validated.

Since testing of equipment surfaces is a major part of the validation of cleaning, a virtual explosion of technology occurred in which techniques and technologies were developed and applied explicitly to the cleaning process. It was no longer acceptable to use a relatively insensitive colorimetric and ultraviolet test for cleaning samples. Likewise, it was not completely acceptable to "test until clean" a process whereby samples were repeatedly tested until a certain acceptable level was achieved. More testing was done by powerful, sensitive, and sophisticated instrumental methods of analysis such as high performance liquid chromatography (HPLC), total organic carbon (TOC), mass spectrometry, enzyme linked immunosorbant assay (ELISA), near-infrared spectroscopy (NIR), grazing angle FTIR spectroscopy, and Ion Mobility Spectrometry (IMS).

There were also many refinements made in the sampling technology and sampling technique. It was generally recognized by the scientists in the laboratories that the power of the analytical technique could not overcome poor sampling technology and inadequate sampling techniques. Specific companies emerged that provided high quality swab samples which were guaranteed to not interfere with the analysis of the samples. For example, first generation swabs often contained adhesives, binders, plasticizers, and other chemicals that interfered with the new sensitive analytical methods, thus giving false positive and negative results when used in combination with the new sensitive analytical techniques such as TOC which may have detection limits of 50 parts per billion and lower. Also, the variability in results achieved in early swabbing studies indicated that swabbing did not give a true indication of the amount of residues on the equipment. Due to the nature of the surfaces (roughness, porosity, scratches), the swabbing process did not remove the entire residue from the equipment, i.e., it is recognized as being an incomplete process. Thus, it became necessary to know the efficiency of the swabbing process in order to determine the true amount of residue remaining after cleaning. These so-called recovery studies were used to "correct" the data and calculate the true amount of residue remaining. Recovery factor determination is now both a regulatory expectation and an industry standard for cleaning studies and currently all 'state-of-the-art' laboratories are very familiar with the recovery concept.

Potential microbial contamination of equipment assumed a prominent role in the cleaning validation program. This posed an entirely different type of challenge since microbial residues are not visible at the level that can be medically significant. Although microbial analysis had been used for many years for sterile products and aseptic processing, it had not been adequately considered as a potential quality problem for non-sterile manufacturing facilities. Only in the last few years have scientists begun to apply the principles of microbiology to non-sterile facilities. Early indications are that this will be a product-specific situation where certain products and manufacturing facilities will require more microbial scrutiny because of the nature of the product and how it is used by the patient or consumer.

Each company will need to assess the potential for microbial contamination to compromise either the safety of the patient or the performance of the product. In some cases, microbial issues will not be significant because of the nature of the product, how it is used, or the current controls that are already in place to prevent adverse microbial events. For example, a company that manufactures products that do not support microbial growth and are used topically on intact skin may not require microbial studies. In other cases, because of the components in the product or how the products are used, microbial studies may be required in order to verify that the current cleaning procedures are adequate to prevent adverse events in the patient or product quality problems. For example, if the pharmaceutical products contain natural materials such as proteins and sugars which can support microbial growth, then microbial studies may be entirely appropriate. Another contributing factor is the equipment itself and how effectively the equipment is disassembled, cleaned, and dried. This is another important source of potential microbial contamination of products. The important point is that each company will need to determine the potential risk of microbial contamination and its possible consequences for their particular products. Much work has already been done by scientists to provide a high assurance that certain classes of products are probably highly unlikely to be affected by pathogenic organisms (reference to work of Jose Fernandez) either because of the inherent hostile environment for microbial growth created by the product itself or because of a lack of moisture to sustain or support microbial growth.

CLEANING PROGRAMS OF THE FUTURE

Having considered the past and current cleaning issues, it is appropriate to look to the future as to what can be expected based on the momentum of current cleaning programs as well the general health and public welfare. One of the most significant emerging truisms is that cleaning of pharmaceutical equipment and facilities is an integral part of product quality as well as a major parameter in the health equation. One can only speculate as to where we are headed with cleaning, but I would like to give you my assessment of what is logical, practical, scientific, and probable.

First of all, I believe the cleaning programs of the future will start with each company embarking on a fact-finding mission to learn more about their products, how they are used by their customers or patients, how they could be misused, how they are stored, controlled, and further processed. I was amazed a few years ago when auditing suppliers of Active Pharmaceutical Ingredients (APIs) to find that many of the API manufacturers were not aware of the specific manner (dosage form, daily doses, how administered, etc.) in which their customers, the dosage form manufacturers, actually used the APIs and thus in what manner they were used by the patient or customer. My personal opinion is that the ideal process will start with risk assessment. I further believe that the risk assessment must be comprehensive and should be more global in nature, that is: that it should consider the product activities both inside and outside the manufacturing facility. It should be 'cradle to grave' in nature.

Risk assessment should be done in phases. First, at the most general level, each company should ask and answer basic questions:

* Do I need to protect the raw materials, intermediates, and products from other products? How do I do that?

* What is the potential for cross contamination of products? What controls are in place to prevent, minimize, or detect these cross contaminations?

* Do I need to protect the operators from the products? How do I do that?

* How am I protecting the environment from the raw materials, intermediates, and products? And how am I protecting the raw materials, intermediates, and products from the environment?

* How can I prevent intentional criminal or bioterrorism contamination of my products? What controls and methods of detection of contamination or tampering are in place to ensure my product reaches the patient or consumer without contamination or degradation?

Once these basic risk questions and answers are evaluated, then more specific questions can be addressed and the branching can continue much as a decision tree might look. The details of the additional phases of risk assessment are beyond the scope of this article, but obviously should include identification of worst case products, most difficult to clean equipment, and examination of locations where contamination and cross contamination are most likely to occur.

The risk assessment should be quantitative. If risk is too high, what can be done to reduce the risk? What controls can be put in place to reduce the risk? It is already obvious that if minimization of cross contamination is one of the main goals, then there must be greater control of potent and potentially toxic products than for less potent products. However, if protection of all products from tampering, bioterrorism, or intentional contamination is the goal, then a different approach or strategy must be used and looking solely at the cleaning of the most potent product(s) would not suffice.

The point here is that the result of the risk assessment should be the development of a strategy which is directed toward achieving finite goals. In some cases, the goal may be to clean the equipment. In other cases, it may be to contain the product. Recently, there have been numerous studies documenting the exposure of health professionals to cytotoxic and other potent products. (References 3-7) In these cases, significant blood levels of potent products were found in blood and urine specimens of doctors, nurses, pharmacists, and other health professionals involved in the administration of potent drugs to patients. The articles speculate that the entry routes are via the skin, lungs, and oral pathways. In some cases, residues of drugs have been found on the outside of vials and ampoules of injectables. Another theory that has been offered is that during the removal of air from injections immediately prior to injection, micro-aerosols of the product may be "injected" into the environmental air and then breathed in by the health professional.

Much of the control of cleaning will depend on the availability of fast and sensitive analytical and testing technology. It seems to me that we may want to learn from the food and beverage industry in some of these areas. In many of the trade publications for food safety there is currently tremendous interest in the rapid testing of food processing surfaces for microbiological residues. This is important because of recent contaminations of various foods both domestic and imported. There is a need to know, on a continuing and rapid basis, that our food processing equipment surfaces are free of microbial contamination. One has only to pick up a copy of Food Safety Magazine, a trade publication, and review the advertising for available rapid microbial testing methodology. Most of these are based on the ATP bioluminescence principle and involve swabbing the equipment with a special swab which is then exposed to chemicals that amplify and quantitate the bioluminescence.

I believe that in the future we will be doing the same sort of swabbing of our pharmaceutical equipment immediately prior to use. This will help us in many ways. We often clean equipment and then it may become recontaminated during long idle periods of storage time. If those surfaces have become contaminated either accidentally or even intentionally (bioterrorism) would it not be a great control to be able, not only to test the equipment, but to constantly monitor the condition of these critical equipment surfaces? I believe this is at least related to the goals of the process analytical technology (PAT) FDA initiative to constantly monitor our critical processes. Again, the cleaning process must be considered, in my opinion, just as critical as the manufacturing process.

In addition to the emerging rapid testing for microbial residues, there is currently an emphasis being placed on the rapid analysis for chemical residues. The "need for speed" is the same as for airport security units that must process passengers for thousands of domestic air flights each day. The evaluation must be fast since people are lined up and waiting to board their planes and they must be sensitive in order to detect the trace levels of telltale residues. The technology used again involves swabbing of carry-ons, typically laptop computers, and evaluation of the swab by an analytical device that accomplishes the scan in microseconds. Some rapid and sensitive techniques that are currently under study include ion mobility spectrometry (IMS) and diffuse reflectance spectroscopy (DRS).

SUMMARY

The pharmaceutical industry has come a long way over the brief 50 year time span that I have worked in it, but the next 50 years truly promise to be even more exciting and more demanding. The risks are enormous, the responsibility is huge, and the stakes (the quality of our products and the health of the nation) are the highest they have ever been. Cleaning, containment, control--the 3 C's--will continue to be important in achieving and improving the quality of our products and thus the health of our people.

My best wishes for your happiness, health, and productivity in your chosen profession, my friend. Take good care

REFERENCES

1. FDA, Current Good Manufacturing Practices for Finished Pharmaceuticals, Title 21, Vol 2, Part 211.

2. FDA, "Guide to Inspection of Validation of Cleaning Processes" (Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs) (July, 1993).

3. Preventing Occupational Exposure to Antineoplastic and other Hazardous Drugs in Health Care Settings, National Institute for Occupational Safety and Health (Sep 2004).

4. Baker, E.S and T.H. Connor, Monitoring Occupational Exposure to Cancer Chemotherapy Drugs, American Journal of Health System Pharmacy (Nov 1996).

5. Robays, M, the Pharmaceutical Journal, Vol 263, No 7070 (Nov 1999).

6. Kaijer, G.P., W.J.M. Underberg, and J.H. Berjnen, Risks of Handling Cytotoxic Drugs, Pharmacy World and Science Journal (May 1990).

7. U.S. Department of Health and Human Services, Centers for Disease Conrol, National Institute for Occupational Safety and Health, "Guidelines for Protecting the Safety and Health of Health Care Workers," Publication No. 88-119 (1988).

ABOUT THE AUTHOR

Dr. William (Bill) E. Hall has over 45 years industry experience in areas including Research and Development, Quality Assurance, and Quality Control. Bill is a member of the JVT Editorial Advisory Board and has given hundreds of presentations on the subjects of process and cleaning validation, quality assurance and compliance, as well as drug abuse. He serves as an expert witness for the FDA in the area of GMP compliance and has taught FDA inspectors in the evaluation of cleaning programs. Before entering industry, Bill worked in academia for seven years as a professor at the University of North Carolina at Chapel Hill in the School of Pharmacy. Dr. Hall can be reached by email at CleanDoct@aol.com or by phone at 910-458-1087.

Article Acronym Listing

API    Active Pharmaceutical Ingredient
DRS Diffuse Reflectance Spectroscopy
ELISA Enzyme Linked Immunosorbant Assay
FDA Food and Drug Administration
GMP Good Manufacturing Practice
HPLC High Performance Liquid Chromatography
IMS Ion Mobility Spectrometry
NIR Near Infrared Spectroscopy
PAT Process Analytical Technology
QA Quality Assurance
QC Quality Control
TOC Total Organic Carbon


BY WILLIAM E. HALL, PH.D.

A Personal Tribute to Ken Chapman

Approach for performance qualification of cold rooms and chambers

Cold storage is a relatively simple cold room that is commonly used to store material between 2[degrees] to 8[degrees]C. Such cold rooms are now available commercially as walk-in chambers and are used for the storage of critical pharmaceutical products, samples, and raw materials where excursions in temperature conditions may affect the quality of stored material(s) in terms of their appearance (color), consistency, potency, and impurity levels. Hence it is essential to qualify cold storage chambers under the worst-case scenarios.

Some pharmaceutical manufacturers perform only Installation Qualification (IQ) and Operational Qualification (OQ) of cold rooms, but the Performance Qualification (PQ) is also essential because data-based conclusions should be arrived at by challenging the system for all the attributes that may have bearing on the performance of the chamber for maintaining the desired temperature conditions.

OFFICIAL AND STANDARD REFERENCES

USA

21CFR 211.142 and 211.150: Storage and Distribution

USP Chapter 1079: Good Storage and Shipping Practices

"Qualification of cold equipment or stores"--On a regular basis, qualification procedures should be independently conducted on equipment in cold stores to guarantee their suitability and proper functioning. The procedure should demonstrate the temperature profile for both air and product temperatures when chambers are empty as well as when loaded. The procedure should also demonstrate the time taken for temperatures to exceed the maximum temperature in the event of a power failure. Qualification should consider thermal fluctuations that occur during stock replenishment and order removal. The results of the qualification should demonstrate the ability of the equipment to maintain the required temperature range in all areas, defining any zones which should not be used for storage such as those areas in close proximity to cooling coils, doors, or cold air streams from equipment ventilation. The variability of the system can be characterized by using the relative standard deviation. Thermal monitoring should establish that the system is rugged in that its temperature profile is consistent and reliable.

Medicines and Healthcare Products Regulatory Agency (MHRA)

Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007, Section IV "Guidance on Wholesale Distribution Practice" pg 358:

"Large commercial refrigerators and walk-in cold rooms should be monitored with an electronic temperature--recording device that measures load temperature in one or more locations, depending on the size of the unit.... Internal air temperature distribution should be mapped on installation in the empty and full state, and annually thereafter, under conditions of normal use."

Irish Republic

Irish Medicines Board: Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances PDA Technical Report No. 39

Cold chain guidance for medicinal products: maintaining the quality of temperature-sensitive products through the transportation environment.

World Health Organization

Guidelines on Good Distribution Practices (GDPs) are incorporated into volume 2, good manufacturing practices and inspections, in "Quality Assurance of Pharmaceuticals."

Canada

Food and Drug Regulations, Section C.02.015 Guidelines for Temperature Control of Drug Products during Storage and Transportation (Guide--0069)

* Storage is a critical parameter in maintaining the quality, safety, and efficacy of a medical product.

* Storage condition is an important parameter to maintaining the stability of the product.

* Product must be stored in accordance with the requirements of its marketing authorization.

QUALIFICATION PARAMETERS

Normally, the Design Qualification (DQ), Installation Qualification (IQ), and Operational Qualifications (OQ) of the cold room are performed prior to the Performance Qualification (PQ). The IQ/OQ of the chamber are easy to perform and document, and a majority of pharmaceutical manufacturers comply with this requirement. The supplier of the equipment also helps in performing these qualification tests for IQ and OQ.

Now the question arises as to why and how the performance of the cold storerooms or chambers should be qualified.

The purpose of the PQ of the cold room is to establish sufficient data to ensure that the cold room is capable of:

* Maintaining the desired temperature range throughout the cold room under extremes of external temperature.

* Identifying potential hot spot(s) or cold spot(s) in the chamber.

* Determining the time required for conditions to return to specified parameters (as desired) in case of excursions.

* Determining the effects of electrical or refrigeration source fluctuations or power failure--especially where back-up units are employed.

While designing the validation study (protocol), understanding the design of the cold room is helpful. A cold room or chamber is a room in the shape of a cubical, made with prefabricated Polyurethane Foam (PUF) insulated panels or of brick and mortar with insulation to maintain the desired conditions of temperature and humidity within. Knowing that the seal between any two panels is integral, and that there are no openings, other than the door, which may disturb the conditions of the chamber. Understanding of the design of the chamber is needed to decide on the number of probes and their locations for temperature monitoring.

Parameters that may affect the Condition of the Cold Room

It is desired that the cold room chamber provide controlled temperature conditions. There are several parameters that may have an impact on the condition of the cold room. These include:

* External temperature conditions

* Door opening time during handling of material in and/or out of the Cold Room

* Power breakdown

* Air flow velocity through fans (not less than 2400 CFM (cubic feet per minute))

* Too much material stored in the room (thermal load)

Therefore, during the PQ study the above listed parameters should be subjected as simulated worst-case conditions because these parameters may have an impact on the performance of the cold room.

TEMPERATURE MAPPING

The temperature mapping is accomplished by using temperature indicating probes coupled with a data logger for data accusation. Questions may be asked regarding the number of probes to be utilized and their placement in the cold room for temperature mapping in the empty room and the loaded room. The basic consideration should be that the probes are distributed uniformly in the room and should cover all the vertical planes. A minimum of fifteen (15) probes were considered adequate for mapping of the temperature of the cold room to verify its performance (1).

Justification for Probe Locations

Probe location should be decided logically, strategically, and scientifically. The following locations cover the entire room:

Probe No 1:

External environment outside the cold room

Probe No 2:

To calibrate along with the in-built temperature and humidity probe of the room

Probe No 3:

Near to the door opening

Probe No 4:

At the centre of the room

Probes No 5, 6, 7, 8:

Top layer four corners of the room, but not at the extreme corners

Probes No 9, 10, 11, 12:

Bottom layer four corners of the room, but not at the extreme corners

Probe No 13:

In mid-region between the door and Probe No 4

Probe No 14:

In mid-region between back of wall and Probe No 4

Probe No 15:

In mid-region between floor and Probe No 4

By placing the probes in these positions, you will completely cover the room and all the planes of the cuboid (chamber). Such mapping is also conducted as an operational qualification to check whether the components or utilities are capable of providing the desired conditions.

PERFORMANCE QUALIFICATION STUDIES

For performance qualification, two separate studies are required to be performed. One study should be completed for the temperature distribution in an empty room or chamber running continually for 24 hours. The second would be a temperature distribution study in a loaded room or chamber. Load the boxes with material that simulates a thermal load, such as starch, lactose, or water in bottles (in case liquid is to be stored in the chamber) record the temperature intermittently for 75 hours each, for three seasons (i.e., peak Summer, Monsoon (as applicable), and Winter) to demonstrate that there is no effect of seasonal variations on the temperature controls in the cold room.

STUDY METHODOLOGY

For Blower Performance

The CFM of the blower should be checked and recorded at each prequalification (PQ) test point. This information shall help to decide whether the air circulation from the blower is the cause, if the condition is not achieved at one or more locations, or it is the cause of the loading pattern of the materials in the chamber, where the temperature is being monitored.

[FIGURE 1 OMITTED]

For Empty Room or Chamber

Set the temperature of the cold room at the desired temperature and operate the cold room according to Standard Operating Procedure (SOP). Perform temperature mapping for 24 hours with five minute sampling intervals. After completion of the study, review the data to identify the hot spot and cold spot areas in the cold room.

For Loaded Room or Chamber

Load the entire room with dummy boxes (as described earlier under "PERFORMANCE QUALIFICATION STUDIES") on the pallets or racks up to its 80% capacity, maintaining gaps between boxes for uniform circulation of air. Set the temperature of the cold room at the desired temperature and operate the cold room according to SOP. Perform the temperature mapping for 72 hours with five minute recording intervals. After completion of the study, review the data and identify the hot spots and cold spots in the loaded cold room.

SIMULATIONS

The following worst-case conditions should be simulated:

For Power Failure Condition

A power failure study should be conducted at a peak temperature hour in summer. When the cold room is in operation and within the set temperature level, switch the power off from the mains. Record the temperature at intervals of one minute for simulation of conditions of power outage.

Continue recording the temperature until the temperature within the chamber falls outside the acceptance criteria. When the temperature is out of limit at the hot spot area identified earlier in the study, switch ON the mains and continue recording at intervals of one minute until the desired temperature is achieved. Record the time required for conditions to go beyond the limits from normal under the simulated situation of power failure, and again, the time required for regaining the desired conditions upon power resumption.

For Open Door Condition

The open door condition study should be conducted at a peak temperature hour in summer. When the cold room is in operating condition and the temperature is within the set value, open the door and record the temperature at intervals of one minute. With door open, continue recording the temperature until the temperature within the cold room is out of acceptance criteria.

When the temperature is out of limit at the hot spot identified earlier in the study, close the door and continue recording until the desired conditions are regained. Record the time required for conditions to go beyond the limits, from normal under the simulated situation of the door being opened and the time required to regain the desired conditions upon closure of the chamber's door.

RE-QUALIFICATION

Performance Qualification of cold room to be requalified for:

* Replacement of existing room component with a new one, which can have a direct impact on the performance of the cold room.

* Any major modification in a key machine (such as the compressor) which can affect the performance of the cold room.

The PQ should be conducted annually under normal usage.

CONCLUSION

The temperature for the cold room or chamber is the critical parameter, since excursions in temperature conditions may affect the quality of stored material(s). It is essential, therefore, to qualify cold room performance under worst-case scenarios. The approach described above for conducting the performance qualification of such cold rooms or chambers, with the consideration of all possible challenges that may have a bearing on the desired acceptance criteria addresses each potential issue. Conducting the studies following the methodology outlined, the impact of situations such as opening the door, or power failure for a given period can be known. Further, through these procedures, it is possible to identify the hot spot and cold spot and the time required to regain the desired temperature conditions if disturbed because of adverse conditions.

REFERENCES

1. Michael J.A., Anderson N.R., "Sterilization Validation." In R.A.Nash, A.H.Wachter, eds., Pharmaceutical Process Validation 3rd Ed. New York: Marcel Dekker, PP. 100(2003).

2. Food and Drug Administration, 21CFR 211.142 and 211.150 (Storage and Distribution).

3. The United States Pharmacopeia, Chapter 1079: Good Storage and Shipping Practices.

4. Medicines and Healthcare Products Regulatory Agency, Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007, Section IV "Guidance on Wholesale Distribution Practice" pg 358.

ABOUT THE AUTHORS

Francis Fernandes is Quality Assurance Manager of Glenmark Pharmaceuticals Ltd, Colvale, Goa, India. He has over eight years in the pharmaceutical industry in areas that include manufacturing, technical services, and Quality Assurance. Mr. Francis Fernandes specializes in the validation of equipment, utilities, manufacturing, cleaning, and product processes. He can be reached by e-mail at fransha.ape@gmail.com, francisf@glenmarkpharma.com

Dr. Subhash Pande is Vice President Corporate Quality Assurance, in Glenmark Pharmaceutical Limited, Mumbai. Having over 20 years of experience in manufacturing, Quality Assurance of APIs, Sterile, Oral, and Semi-solid Oral dosage forms, Teaching and Research. A life member of Indian Pharmaceutical Congress and ISPE, he has more than twelve research papers published in National and International journals. He is also associated with IBC Asia, for training. He also is involved in academic activities in the capacity of Guest Lecturer and as Examiner. He can be reached by email at subhashp@glenmarkpharma.com or subhashp@gmail.com.

Article Acronym Listing
1.2   Objectives
The objective is to provide guidance on how to carry out the three types of qualification needed to meet the requirements of Good Storage Practice in temperaturecontrolled areas.  These are Installation Qualification (IQ); Operational Qualification (OQ), and Performance Qualification (PQ).
1.3   Target readership
This document is relevant to wholesalers, warehouse operators, distributors, dispatchers and 3PLs who store TTSPPs. The specific target audience within these organizations includes those who have direct responsibility for quality management, for example, Quality Assurance (QA) Managers and Operations Managers.
2. Guidance
The purpose of qualification in the pharmaceutical and medical sector is to ensure that equipment or ancillary systems are properly installed, work correctly, and produce the specified performance outcomes under routine operating conditions.
2.1   Associated materials and equipment
A qualification operation requires a sufficient number of electronic data logging monitors (EDLMs) to ensure that qualification activities can be carried out correctly. In addition, suitable computer equipment and software is needed to store and analyse the data. The chosen EDLMs should have the following characteristics:
•           Be technically suitable for the specific task and the intended operating
environment;
•           Provide a reliable and continuous reliable record of time-temperature data;
•           Have an appropriate temperature range so that all anticipated temperature
extremes can be recorded (e.g. from -30°C to +60°C).
•           Have a user-programmable data sampling period with time intervals ranging from
one minute to 15 minutes or more;
•           Have a NIST- traceable 3-point calibration certificate and have a guaranteed error
of no more than ± 0.5°C at each calibration point.
•           Recorded time-temperature data should be downloadable to a computer system
for subsequent analysis;
•           Data storage and analytical software should comply with applicable regulatory
requirements (e.g. FDA 21 CFR part 11).
2.2   Introduction to qualification
Qualification is part of validation, but the individual qualification steps do not in
themselves constitute process validation. Validation is the entire process by which a
product is obtained from a manufacturer or distributor and is examined and tested before it is formally approved for routine use.
A qualification exercise generally consists of three sequential phases: Installation
Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).
a.   Installation Qualification: The purpose of installation qualification (IQ) is to ensure             that a new piece of equipment - together with all its related systems or sub-
systems - has been installed in accordance with the relevant installation drawings and specifications.
b.   Operational Qualification: A successful operational qualification (OQ) exercise
provides assurance that equipment which has successfully passed the IQ stage
operates in an effective and consistent manner. As a general rule, OQ is carried out on equipment when it is empty.
c.   Performance Qualification: Following OQ, a performance qualification (PQ)
provides additional assurance through further testing that the equipment will
work correctly in the intended operational setting. The outcome of a successful PQ
exercise is a formal confirmation that the equipment, associated systems and operational processes can be ‘released’ for routine use.  In contrast to OQ, PQ is carried out on equipment when it is full.
2.2.1   Qualification applied to temperature-controlled storage
Qualification is commonly used to validate pharmaceutical manufacturing processes but it can also be applied to the pharmaceutical supply chain in general, and to temperaturecontrolled storage processes and equipment in particular.
In this later context, temperature-controlled storage covers any area where TTSPPs have to be stored within a controlled temperature range (e.g.: 2-8°C, 15-25°C).  This includes:
   Active temperature-controlled storage equipment, including ultra-low freezers,             freezers, freezer rooms, refrigerators, cold rooms and controlled-ambient stores.
   Actively temperature-controlled transport equipment. This includes refrigerated             and temperature-controlled trucks and vans, refrigerated and temperature-
controlled ocean containers.  Refer to the companion Technical Supplement: Qualification of temperature-controlled road vehicles.
   Passive temperature-controlled packaging systems (shipping containers). This             includes insulated containers used to maintain product temperature during road
and air transport. Refer to the companion Technical Supplement: Qualification of shipping containers.
All temperature-controlled equipment and systems used to handle, store and distribute TTSPPs should be qualified.
An integrated IQ, OQ and PQ procedure is commonly used to qualify temperature-
controlled storage areas. Ideally the IQ, OQ and PQ procedures should be applied in a progressive and coordinated way, from the installation up to the final performance verification. However this may be more difficult if the storage areas and equipment are already in use.

2.2.2   Installation qualification
The IQ process should be completed first. Its purpose is to ensure that the storage area
and all its associated equipment and systems are clearly identified and have been correctly installed. This step must be completed before any further functional or operational tests are carried out.
Specifically, an IQ process should:
a.   Identify the storage area and the equipment and systems required for it to operate             correctly. Establish that all systems operate as specified;
b.   Establish the calibration status of all measuring devices (e.g. controllers and             sensors);
c.   Ensure that standard operating procedures (SOPs) or work instructions are up-to-             date and fit for purpose;
d.   Ensure that an effective preventive maintenance programme is in place.
2.2.3   Operational and performance qualification
Once the IQ stage has been completed, the OQ and PQ can generally be carried out
together as a single sequence of inspections and tests. These inspections and tests should be chosen to suit the specific characteristics, performance needs and operational conditions of the storage area being qualified.
Operational qualification is carried out with the storage area empty. It typically involves the following activities:
   Control panel tests and checks;
   Alarm system tests and checks;
   Assessment of temperature control and temperature distribution in the empty             storage space or equipment8;
   Power failure tests and checks.
Performance qualification is carried out with the storage area fully operational, loaded and allowed to reach stabilized conditions. The following tests and checks should be carried out:
   Temperature control and temperature distribution.
   Temperature recovery following a door opening.
2.3   Qualification protocols
Prepare, review and approve a detailed and comprehensive protocol before the qualification process begins.
The qualification protocol should be a comprehensive document, which guides the user through the IQ, OQ and PQ processes and helps ensure that all temperature-controlled storage areas are correctly qualified. Each of the three protocols can be more or less generic. However generic documents should never be used unthinkingly; they should always be adapted to the specific type of temperature-controlled storage area; each installation must be linked to and qualified against its own specific qualification protocol.
The qualification protocol should include the following sections:
a.   Approval page and change control history.
b.   Acronyms and glossary.
c.   Description and rationale.
d.   Scope and objectives.
e.   Key parameters.
f.          Procedures.
g.   Qualification report template.

2.3.1   Approval page and change control history
Include a standard template for recording approvals and changes to the document. The following is an example

Approvals
Name
Date
Signature
Authorized by:



Reviewed by:



Revised by:



Original author:




Version history

No
Date
Description of change
Reason for change
1

Original

2



3



4



5



If the protocol has been prepared by a qualified third-party, it should be authorized by the responsible person within the commissioning organization.

2.3.2   Acronyms and glossary
Define the acronyms and technical terms used in the protocol.

2.3.3   Description and rationale
Describe the installation to be qualified and the equipment and related systems to be
included in the qualification exercise and outline the reasons for carrying out the exercise.

2.3.4   Scope and objectives
Clearly define the scope and objectives of the qualification exercise.

2.3.5   Key parameters
Describe the key parameters for the operation of the installation.

2.3.6   Procedures
The protocol for a specific installation should describe every relevant test or check procedure in detail, as follows:
a.   Title: Briefly describe the test or check;
b.   Target: Name the target system, sub-system or component;
c.   Procedure: Clearly describe the test or check procedure as a step-by-step process.             Specify any associated materials or test equipment required;
d.   Acceptance: Define the acceptance criteria;
e.   Data collection: Include templates for all required data collection and test sheets. A generic set of IQ, OQ and PQ tests and checks is outlined in sections 2.4 to 2.7 below.
2.3.7   Qualification report template
The protocol should contain a template for the qualification report. This should include everything needed to satisfy internal compliance rules and regulatory requirements, as follows:
a.              Introduction: Describe the objectives of the qualification exercise.
b.              Summary: Outline the results of the qualification exercise. Include a summary of all
recorded deviations.
c.          Conclusions and recommendations: State whether the installation can be used for
routine operations. List all key recommendations that need to be acted upon; this should include a complete list of all changes that need to be made to the installation to correct reported failures recorded on the qualification inspection and test data sheets.
d.             Report annexes: Append the following supporting material:
−    Raw data as recorded on the appropriate inspection and test data sheets (see             below). In addition, include all associated spreadsheets and graphs.
−    Key documents and notes prepared during the qualification exercise, together             with any other supporting material.
−    Deviation reports, including Corrective and Preventive Actions (CAPA) forms, if             required.
−    Calibration certificates for all EDLMs used.
−    Calibration certificates for the control and monitoring systems that form part             of the installation.
−    List all members of the qualification team, and their designations.
All data sheets, results, spreadsheets and graphs must be reviewed by an independent person who was not involved in conducting the qualification exercise. The reviewer should confirm, approve and sign results of the major tests and checks.

2.3.8   Approval process
If qualification is carried out as an in-house process, the IQ/OQ/PQ protocols and
subsequent qualification reports must be authorized by the responsible manager(s) and quality assurance personnel within the organization.
If qualification is carried out by a qualified third-party, both the IQ/OQ/PQ protocols and subsequent qualification reports must be approved by the responsible person in the thirdparty organization.
2.4   Installation qualification
The purpose of installation qualification is to establish that all elements of the storage area, including building work, equipment, systems, sub-systems and components are in accordance with the installation drawings and specifications. The first stage is to itemise all these key elements. The next stage is to establish how each element should be inspected and tested in order to confirm compliance.
Once these preliminary stages have been completed, on-site inspection and testing can begin. Proceed as follows:
•           Carry out a detailed inspection of the storage area and all associated building
works.
•           Carry out a detailed inspection of the electrical services.
•           Carry out a detailed inspection of the mechanical services.
•           Carry out tests to confirm that the specified environmental condition requirements
have been met.
•           Identify, list and inspect the spare parts  supplied as part of the installation.
•           Identify, list and inspect any auxiliary equipment associated with, but not part of
the installation, such as standby generators, security systems and the like.
•           Confirm that satisfactory arrangements are in place to ensure an effective
preventive maintenance programme for the complete installaton.

2.4.1    Identifying critical components
Although all parts of a temperature-controlled installation should be included in the IQ, there are certain critical elements that merit particularly close attention.
Refrigerators, freezers and other simple equipment: The critical parts of this type of
equipment are the thermostat and its associated control sensor and the temperature monitoring device (thermometer or recorder) and its sensor; this may be a separate component such as a disposable 30 day temperature recorder9.
Complex equipment: This includes freezer rooms, cold rooms, pick coolers and more
complex and specialized refrigerators and freezers, with a longer list of key components. Critical parts include the controller, sensor, cooling unit, condenser and evaporator.  For freezer rooms and cold rooms, the room enclosure itself is also critical because these are site assembled from separate panel elements10. All of these key components should be identified, listed, described and checked.
If the equipment has duplicate or multiple instances of any components or systems, each one should be checked. Critical components and systems that are directly involved in temperature control and measurement should also be checked for accuracy and calibration. Calibration certificates should be checked and copies included in the IQ report.

2.4.2   Checking installed systems, sub-systems and components
Table 1 shows the type of record used to check and record installed systems and components. The example given here is for a cold room refrigeration unit.
Table 1 - Example of an IQ inspection and test table

Sub-system or component inspection and test table
Location:
SOUTH WAREHOUSE
System:
Cold room #1
Sub-system/component:
Refrigeration unit #1
Inspection or test:
Inspection:
Test:
Type of inspection/test:
IQ protocol: visual check RFU-01
Details:
Specified
As found
Pass or Fail
Manufacturer:
ABC refrigeration
ABC refrigeration
Pass
Model:
TTW50
TTW40
Fail
Serial number:
Not specified
TTW40-1310-025
Fail
Internal ID number:
CR1/RFU01
CR1/RFU01
Pass
Deviation report ref:
Enter ‘none’ if no deviation
DEV/001
Inspected by:
AG
Date:
27 Oct 2013
Checked by:
JB
Date:
5 Nov 2013
For each system, sub-system or component, the table allows the IQ inspector to list the
critical attributes of what was originally specified in the requirements specification or on the installation drawings (the ‘specified’ column), what was actually installed (the ‘as found column) and whether or not it complies (the ‘pass or fail’ column).
a.              Specified conditions: The ‘location’, ‘system’, component’ cells and the ‘specified’
column should be completed before the inspection begins. The same applies to the subsequent Tables 2 to 4. Pre-filling the table helps the IQ inspector to locate the listed item and check that it has been installed correctly. Where details are not
available - in the above example the serial number of the refrigeration unit - enter ‘not specified’.  In addition, record whether an inspection and/or test(s) are to be carried out to assess compliance and describe the type of inspection and/or test(s)
to be used. Key this back to the relevant section of the qualification protocol.
b.              As found column: Use this column to record details of the item as found at the time
of the inspection.  To achieve a ‘pass’, the installed sub-system or component must meet or exceed the specified condition. In the Table 1 example, although the refrigeration unit has been supplied by the specified manufacturer, the unit installed has a lower power rating than the one specified.
c.          Pass or Fail column:  Compliance is achieved when an item fully meets or exceeds
the specification or the specified performance conditions. In the Table 1 example, the correct manufacturer has supplied the unit, so this is a ‘pass’. However, the refrigeration capacity of the installed unit is too small, so this is a ‘fail’
.   Deviation report: Wherever a deviation is observed, this must be recorded on a             separate deviation report form. Each inspection table should include a space to
record a cross-reference to the relevant deviation report. If there are no deviations, enter ‘none’ - see example of deviation report in Annex 1).
e.   Signatures:  The completed sheet should be signed or initialled by the inspector             and checked by the designated reviewer.
Use drawings, photographs and other supporting material to amplify and support the information recorded in the table.

2.4.3   Checking electrical systems and requirements
Because the installed electrical system typically connects to multiple components, it
requires a separate inspection and qualification procedure. Table 2 can be used to record the overall compliance of the installed electrical system. Table 3 is used to identify and check the critical components of the system.
Table 2 - Overall compliance check for electrical installation

Electrical installation: system compliance check  sheet
Location:
SOUTH WAREHOUSE
System:
Electrical installation
Sub-system/component:
3-phase supply to cold room #1
Inspection or test:
Inspection:
Test
Type of inspection/test:
IQ protocol: visual check ELEC-01
Items
Specified
As found
Pass or Fail
Main voltage (V):
415 V
415 V
Pass
Cycles (Hz):
50Hz
50Hz
Pass
Amperage (A):
100 A
100 A
Pass
Phase:
3
3
Pass
Inspected by:
AG
Date:
27 Oct 2013
Checked by:
JB
Date:
5 Nov 2013
Table 3 - Electrical installation: critical component checks

Electrical installation: critical component check sheet
Location:
SOUTH WAREHOUSE
System:
Electrical installation
Sub-system/component:
3-phase supply to refrigeration unit A
Inspection or test:
Inspection
Test:
Type of inspection/test:
IQ protocol: visual check ELEC-05
Electric supply
Specified
As found
Pass or Fail
Breaker location / service
panel
Panel A
Panel A
Pass
Circuit / breaker number
Not specified
RFU-1
Pass
Circuit voltage (V)
315
315
Pass
Circuit amperage (A)
30 A
20 A
Fail
Circuit phase
3
3
Pass
Emergency power?
Required
Yes
No
Pass
Isolating switch?
Required
Yes
No
Pass
Is the electrical supply
compatible with electrical
requirement?

Required

Yes

No

Fail
Grounded?
Required
Yes
No
Pass
Special isolation /
shielding?
Not required
Yes
No
Pass
Is the circuit breaker
properly identified?
Required
Yes
No
Pass
Inspected by:
AG
Date:
27 Oct 2013
Checked by:
JB
Date:
5 Nov 2013
The service panel and circuit breakers that apply to the various critical components should be clearly labelled both at the service panel itself and at the component.
Table 4 - Environmental condition, control and monitoring checks

Environmental control and monitoring system check sheet
Location:
SOUTH WAREHOUSE
System:
Cold room #1
Sub-system/component:
As above
Inspection or test:
Inspection:
Test:
Type of inspection/test:
IQ protocol: visual check ENV-01 and instrumented
measurement ENV-02
Items
Specified
As found
Pass or Fail
Cleanliness:
All surfaces clean
Floor dusty
Fail
Fumes:
None perceptible
None perceptible
Pass
Vibrations:
None perceptible
RFU #1 vibrating
Fail
Temperature control:
Single sensor
Single sensor
Pass
Humidity control:
No active control
No active control
Pass
Temperature monitoring:
3 sensors
3 sensors
Pass
Humidity monitoring:
None
None
Pass

Temperature (°C):

+2°C to +8°C
+5.5°C (sensor 1)
+6.1°C (sensor 2)
+4.9°C (sensor 3)

Pass
Humidity (% RH):
60% to 75%
70%
Pass
Inspected by:
AG
Date:
27 Oct 2013
Checked by:
JB
Date:
5 Nov 2013
2.4.5   Checking spare parts
If applicable, include a section in the IQ report on change parts and list those that have
been provided as part of the installation. These parts need to be checked for compliance as described above in section 2.4.1.

2.4.6   Checking auxiliary equipment
The installation may have ‘auxiliary equipment’ associated with it, which is not directly included in the scope of the IQ inspection. An example might be a security and alarm system. This equipment should be identified and listed in the IQ report. The report should also include a description of the electrical, electronic or other interfaces between this equipment and the installation itself.
2.4.7   Checking information needed for the preventive maintenance programme
An effective preventive maintenance program (PMP) cannot be implemented unless the relevant key elements are in place. The IQ inspector should check the following:
a.   Is all the equipment and are all key components listed in the equipment inventory?
b.   Are all these items labelled in accordance with the organization’s equipment             management policies?
c.   Is there an equipment inventory file, and where is it located?
d.   Is there a maintenance logbook, and where is it located?
All relevant documentation, drawings and installation and commissioning records should be collected together in an equipment file and attached to the IQ report. Table 5 shows one way to index this information in tabular form.
Table 5 - Equipment file index

Information available in the equipment file

Equipment or
component ID

Equipment or
component name
TS
OI
MI
RS
Record type
Record number






























TS = Technical specifications   MI = Maintenance instructions
OI = Operating instructions     RS = Recommended spare parts list

2.4.8   Writing the IQ report
As soon as the IQ assessment has been completed, prepare a report as outlined above in section 2.3.11. Pay particular attention to the following points:
   Make sure that all of the sections included in the IQ protocol have been completed,             signed and dated.
   Record all deviations from the installation drawings and specifications in the
deviation report section. Make sure that each deviation is cross-referenced to the relevant sections of the IQ protocol.
   Specify the actions that need to be taken to correct the reported deviations and             state the person or organization responsible for completing these actions.
   Transcribe any hand-written notes made by the IQ team into the relevant sections             of the report.
   List all members of the qualification team, and their designations.


2.5   Operational qualification
Do not begin the operational qualification stage until all of the deviations recorded during the IQ inspection have been corrected.
The purpose of operational qualification is to establish that the installation and all its
systems and sub-systems operate effectively and consistently when the storage area is
empty. As soon as the OQ process has been completed and the installation has been
approved, the next step is to carry on to the performance qualification (PQ) stage, with the storage area full.  Once the entire OQ/PQ process has been successfully completed, the installation can be signed off and fully released for routine operation.
An OQ inspection should cover the following points:
•           Check the calibration of all temperature measuring and controlling systems and
components.
•           Test the installation’s control systems and check that these systems function
correctly.  Check the system set points.
•           If there is a temperature alarm system, set the low and high alarm limits and set up
and test the relevant alarm outputs such as email messages, SMS messages and telephone contacts.  Record the results.
•           Carry out a temperature mapping of the empty storage area and record the results.
See Technical Supplement: Temperature mapping of storage areas.
•           Ensure that all relevant standard operating procedures (SOPs) are available, that
relevant personnel have been trained to follow these SOPs and that training records are in place.

2.5.1    Checking installed systems, sub-systems and components
As with the IQ procedure described in section 2.4.2, the OQ inspection and test tables and report should record the specified condition and the as found conditions and should confirm whether the as found condition is a pass or a fail. All deviations should be recorded, and the assessment results should be signed by the inspector and checked by the independent reviewer.

2.5.2   Calibration of controllers and sensors
All the controllers and sensors that form part of the installation should operate correctly and have valid calibration certificates. These certificates should be attached to the OQ report. Controllers and sensors should be suitably tagged so that they can be identified. Each tag should record the component ID, the calibration date and the calibration expiry date.
The objectives of the inspection are to:
   Check that all critical controllers and sensors have been calibrated and that the             calibration status is current.
   Ensure that all these controllers and sensors are added to a calibration and             preventive maintenance programme.
In order to meet the acceptance criteria, every critical controller and sensor should have:
   A current calibration certificate, with the certificate available.
   A calibration that is traceable to national standards.
   An attached calibration tag.
   An individual record in the calibration section of the preventive maintenance             programme.

2.5.3   Standard operating procedures
There should be a comprehensive set of SOPs which cover all relevant aspects of the installation, routine operation and maintenance of the installation.  These should be reviewed as follows:
   Check that that all required SOPs have been written.
   Check that their content relates to the actual installed equipment and the specific             operational requirements of the installation.
   Check that a training programme is in place, based on the content of the SOPs. The following acceptance criteria apply:
   All SOPs must be approved and available.
   All SOPs must be consistent with operational requirements.
   There must be a training record, directly associated with each SOP, to demonstrate             that training has been conducted..
2.5.4   Control panel
The objective of the control panel inspection is to establish that all temperature controls, indicators and other displays operate in accordance with the manufacturer’s specifications. This inspection is equipment-specific and should be drawn up to suit the system that has been installed.
The acceptance criterion is that all these elements are fully operational.

2.5.5   Alarm tests
The purpose of the alarm tests is to confirming that the alarm system operates in
accordance with the design specifications. For temperature alarm systems, there should be one high alarm test and one low alarm test. If the system also has an event alarm system - for example a door open alarm - this should also be tested.
For each test, record the alarm settings and trigger the desired alarm event. Confirm that the alarm system is activated. Activation may be indicated by an alarm sounder or alarm strobe, by a signal to an alarm company which provides a remote monitoring service (SaaS), by SMS or telephone message or by any combination of these - all relevant systems need to be tested.
Once the alarm tests have been completed, record the results on an alarm system test sheet. A simple example is shown in Table 6.  More complex alarm systems will need a more complex test sheet. Table 6 - Alarm system test sheet

Alarm system test sheet

Test

Operation
Compliance
Deviation
report
number
Tested
by

Date
Yes
No
High temperature alarm
Alarm activated.





Low temperature alarm
Alarm activated.





High alarm setting:

Low alarm setting:

Checked by:

Date:

2.5.6   Temperature mapping - empty
The objective of the temperature mapping test is to demonstrate that the installation is
capable of controlling and maintaining a uniform temperature when the storage area is
empty. The complete area should be monitored for a period of at least 24 hours using
electronic data logging monitors (EDLMs). Table 7 shows how the data should be recorded for an operational qualification test.
Table 7 - Test data sheet: temperature distribution


Data logger
ID number
Min. temp.
Recorded
(°C)
Max temp.
Recorded
(°C)
Mean
temp.
(°C)
Within range?


Yes
No
Inspected by
Date
DL-001







DL-002







DL-003







DL-004







DL-005







DL-006







DL-007















DL-XXX







Mapping period starts at (date/hour):

Mapping period ends at (date/hour):

Checked  by:

Date:


Note: The mapping procedure is fully described in the companion Technical Supplement: Temperature mapping of storage areas. However, in contrast to a full temperature mapping exercise, mapping equipment for a qualification exercise only needs to be done once. Table 7 is taken from Annex 1 of that supplement11.
2.5.7   Power failure test
The power failure test relies on the same data logger setup as the temperature mapping test. The objective of the test sequence is to establish and record:
   The length of time during which the installation can maintain the specified
temperature range following a power failure - this known as the holdover time.
   How long it takes the installation to recover within the specified range once power             is restored.
The results of these tests are simply recorded - there is no deviation report. For cold
rooms, freezer rooms and other large temperature-controlled stores12 there are usually no set acceptance criteria to be reached in this test. However, the test data are useful for the store operator for emergency planning and other purposes; for example, planning the installation and operation of standby generators.
Power failure test:
a.   Fixed power failure period: In this version of the test the power is stopped for a
predefined time period - for example, two hours - regardless of whether or not the temperature inside the storage area exceeds the required temperature range. Power is then returned and the time taken for the storage area to recover within the specified temperature range is measured.
Because both these tests may trigger a temperature excursion, carrying them out when the store is full of TTSPPs can place stored products at risk. For this reason it is best carried out during operational qualification when the store is empty.  Table 8 gives an example of a power failure test sheet.



















11 The temperature mapping supplement recommends that mapping should be carried out in both the hottest and coldest months. However, for the purpose of operational qualification, only one mapping exercise is required.
12 In settings with unreliable electricity, holdover is an important performance feature of mains
powered freezers and refrigerators. For WHO prequalified vaccine refrigerators, the holdover time is laboratory tested and reported. See the WHO PQS website at:


Table 8 - Power failure test sheet


Data logger
ID number
Power off
Time temperature was
within range (hh:mm)
Power  on
Time to recover within
range (hh:mm)

Inspected by

Date
DL-001




DL-002




DL-003




DL-004




DL-005




DL-006




DL-007




DL-008




DL-009









DL-XXX




Power turned off at (hh:mm):

Power turned on at (hh:mm):

Checked  by:

Date:

2.5.8   Writing the OQ report
As soon as the OQ assessment has been completed, prepare a report as outlined above in section 2.3.11. Pay particular attention to the following points:
   Make sure that all of the sections included in the OQ protocol have been completed,             signed and dated.
   Record all deviations from the installation drawings and specifications in the
deviation report section. Make sure that each deviation is cross-referenced to the relevant sections of the OQ protocol.
   Transcribe any hand written notes made by the OQ team into the relevant sections             of the report.
   Specify the actions that need to be taken to correct the reported deviations and             state the person or organization responsible for completing these actions.
   List all members of the qualification team, and their designations.

2.6.1   Checking installed systems, sub-systems and components
As with the IQ procedure described in section 2.4.2 and the OQ inspection in section 2.5.1, the PQ inspection and test tables and report should record the specified condition and the as found conditions and should confirm whether the as found condition is a pass or a fail. All deviations should be recorded, and the assessment results should be signed by the inspector and checked by the independent reviewer.

2.6.2   Temperature mapping - full
The temperature mapping exercise described in OQ section 2.5.6 is repeated, but with the storage area normally loaded with TTSPPs. The same arrangement of EDLMs should be used for the PQ mapping as for the OQ mapping.

2.6.3   Temperature recovery after door opening
The purpose of the door opening temperature recovery test is to establish that the
temperature within the store can return to the specified temperature range within the specified time following a door opening event. The following test parameters should be observed:
   The same arrangement of EDLMs should be used as for the OQ and PQ mapping             tests.
   The chosen door open period used for the test should represent actual door
opening behaviour observed during routine operations. If there is a single door, the critical factor is the maximum observed length of opening.  If there is more than one door, the critical factors are the length of opening, the sequence of
opening, and whether more than one door needs to be left open at the same time. The acceptance criterion for this test is that temperature recorded by all the EDLMs located inside the storage area should return within the specified temperature range (e.g. 2°C to 8°C) within 30 minutes after the door(s) are closed at the end of the door opening test sequence. Table 9 shows an example of a door opening test sheet.
Table 9 - Door opening test sheet

Data logger
ID number
Time to return to within specified
temperature range
(min)
Compliance?


Yes
No
Inspected by
Date
DL-001





DL-002





DL-003





DL-004





DL-005





DL-006





DL-007











DL-XXX





Door(s) opened at (hh:mm):

Door(s) closed at (hh:mm):

Checked  by:

Date:

References
•           Cloud, Phillip A. Pharmaceutical Equipment Validation: The Ultimate Qualification
Guidebook. Interpharm Press, 1998.
•           Health Canada (HPFB Inspectorate). Guide0001, Good Manufacturing Practices (GMP), Guidelines - 2009 Edition, Version 2.
•           HealthCanada (HPFB Inspectorate). Guide 0069, Guidelines for temperature Control of Drug Products during Storage and
Transportation. October 17, 2005.
•           United States Pharmaceopaedia: Chapter 1079: Good Storage & Shipping Practices.
•           US Food & Drug Administration (FDA). cGMP Regulations 21 CFR part 210.
•           US Food & Drug Administration (FDA). cGMP Regulations 21 CFR part 211.
•           US Food & Drug Administration (FDA). cGMP Regulations 21 CFR part 820.
•           WHO Technical Supplement. Calibration of temperature control and monitoring devices.
•           WHO Technical Supplement. Temperature and humidity monitoring systems for fixed storage areas.
•           WHO Technical Supplement. Temperature mapping of storage areas.
Revision history

Date
Change summary
Reason for change
Approved














Annex 1 - Deviation and corrective action report form

Report Number:

DEVIATION DESCRIPTION

Documented by:
Date:
IMPACT ASSESSMENT ON QUALIFICATION
Does this deviation have sufficient impact on the qualification to require a
corrective action?
Yes
No

Documented by:
Date:
RATIONALE FOR CORRECTIVE ACTION

Documented by:
Date:
CORRECTIVE ACTION APPROVAL
Name
Signature
Date










RATIONALE FOR CLOSING THE DEVIATION REPORT

Does corrective action resolve the deviation?
(Attach all resulting test data sheets with this report)
Yes
No
Not applicable



Can this deviation be closed?
Yes
No
Name
Signature
Date










Pharmaceutical Validation Documentation Requirements

Pharmaceutical validation is a critical process that ensures that pharmaceutical products meet the desired quality standards and are safe fo...