We live in a new world where users must specify what they want their analytical instruments to do. This discussion will help you figure out how to make sure you get what you need.
We are in a new world where users must specify their analytical instruments. You mean specify a spectrometer? Welcome to a short discussion on the most critical, but often ignored, part of the lifecycle of a spectrometer: Specifying what you want the instrument to do.
This installment is a short discussion on the most critical, but often ignored, part of the life cycle of a spectrometer: Specifying what you want the instrument to do. Not the salesperson, instrument agent, or supplier, but you. Alternatively, if you want to share the blame with others, consider it you and your colleagues.
Honesty time! Let us start this painful discussion by asking, have you ever bought an instrument that did not perform as expected? I'm at the front of the guilty queue and I suspect most of you are standing in the line behind me. Buy in haste and repent at leisure, that's the name of the game.
What do we do with an unsuitable instrument? If it is an absolute lemon, hide it in a cupboard-preferably the farthest away from the boss's office-and then get rid of it at the earliest opportunity. If it sort of works, blame the failure on the supplier as a Monday morning build.
However, do you ever stop to consider why you are in this sorry state? Let's consider some of the possible (pathetic) excuses:
In many companies, this problem is compounded by the end-of-year slush-fund spend. You know what happens, the boss puts his or her head in the lab and says we've got to spend X amount of dollars by the end of the month or we lose it. Panic stations! Your task, should you accept it, is to identify what you are going to buy, obtain three quotes, write a capital request, walk the document around for approval, raise the purchase order, and have an empty box delivered-all within 3–4 weeks. The typical result is an instrument purchased for an undefined use that was bought just to spend budgeted money and avoid unspecified financial consequences. It will sit in a box for an undefined amount of time until the lab gets around to getting it qualified and validated. Will we ever learn?
You will have noticed that I have not mentioned any regulations or quality guidelines, I merely described what has happened in many laboratories when spectrometers and other analytical instruments are purchased. However, not wishing to disappoint you, here are the regulations and quality standard requirements to consider.
Let's start with International Organization for Standardization (ISO) 17025 (1), which is a quality standard for testing and calibration laboratories. Section 5.5 of ISO 17025 includes the following requirements for analytical instruments:
"5.5.2 Equipment and its software used for testing, calibration and sampling shall be capable of achieving the accuracy required and shall comply with specifications relevant to the tests and/or calibrations concerned.
"Before being placed into service, equipment (including that used for sampling) shall be calibrated or checked to establish that it meets the laboratory's specification requirements and complies with the relevant standard specifications."
Note the phrase "laboratory's specification requirements"-not the supplier's but the laboratory's specification. This phrase implies that there can be a difference between the supplier's specification and that required by the laboratory. Now as a lapsed ISO 17025 assessor, the first version of this quality standard had a footnote to this section that stated that the laboratory's specification may not be the same as the supplier's. It has now been subsumed into the main body of the standard. The important point is that a laboratory does not have to follow the supplier's specification to the letter-what does the laboratory want an instrument to do?
Let us move on to the United States good laboratory practice (GLP) and good manufacturing practice (GMP) regulations for equipment and see what they say about specifications. The U.S. GMP regulations for equipment are found in section 211.63 (2) and state, "Equipment used . . . shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance."
The corresponding regulations for GLP appear in section 58.61 (3) and are as follows: "Equipment used . . . shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance."
Both U.S. GMP and GLP require adequate design suitable for intended use or function to the protocol, respectively. Intended use has been interpreted as documenting requirements, otherwise how can you determine what the use will be and verify that it works?
The latest updated version of United States Pharmacopeia (USP) Chapter <1058> on "Analytical Instrument Qualification" (4) has the following statements:
"The first activity is the generation of a user requirements specification (URS), which defines the laboratory's particular needs and technical and operational requirements that are to be met.
The subsequent qualification activities necessary to establish fitness for purpose may be grouped into four phases: design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ)."
It is clear that writing the URS for an analytical instrument is a totally separate activity than the DQ phase. DQ is an activity that confirms that the instrument or instruments you propose to purchase meet the requirements in your URS. You test the requirements in the OQ phase of work. This process was discussed in my "Focus on Quality" column in September 2017 on the new version of USP <1058> (5). The requirement for a URS followed by DQ is also found in clauses 3.2 and 3.3 in EU GMP Annex 15 on "Qualification and Validation" (6).
The problem now comes with a further statement in the new USP <1058>, which states: "It is expected that DQ requirements will be minimal for commercial, off-the-shelf instruments."
Note these words well. Requirements will be minimal. Not zero, not virtual, not imaginary, not verbal, but minimal. Minimal equals written down, documented, recorded, and formal (approved).
Although USP <1058> says that a URS for an instrument is expected to be minimal, what about any associated software used to control the instrument and also acquire, process, store, and report data? Minimal? I don't think so. We have to factor in data integrity requirements as well as the software functionality for the intended use of the instrument. This process is not an exercise in minimalism. The problem is that all the regulations, such as GMP, GLP, and Part 11, were nearly all written before data integrity became a major issue and regulators are now relying on guidance documents to define their requirements for the integrity of data. This year EU GMP Annex 11 and Chapter 4, on computerized systems and documentation, respectively, will be updated specifically to expand requirements and controls expected for ensuring data integrity into law and not rely on guidance.
The configuration of software is important for computerized laboratory systems because the intended use of the software, including data integrity, can only be tested when the application settings have been enabled and documented. For example, segregation of duties, enabling record protection, and turning the audit trail on are all important items to configure. A major problem is that instruments and software can be ordered without involving the quality assurance (QA) data integrity function, whose role should be to see if an application is suitable for use in a regulated environment. Some spectroscopic software applications will not save data automatically and will only do so when a user hits the save button. An optional approach to integrity-pick the spectrum you want to save! Look on the bright side, at least you don't have the worry of deleting all those pesky nonconforming spectra.
The blame game does not just extend to the users in the laboratory. The supplier has an equally important role in the selection process. The new version of USP <1058> also includes requirement for suppliers (4): "To aid the user, suppliers are responsible for developing meaningful specifications for the users to compare with their needs and aid selection."
Hmm, meaningful specifications. To illustrate this point I would like to tell you about a benchtop centrifuge that my colleagues and I were involved in qualifying as part of a larger laboratory project. We had to qualify a benchtop centrifuge that operated at room temperature with a fixed rotation speed and a timer. What instrument could be simpler to qualify? However, the rotor speed was specified as 3500 ± 1 rpm. What!? One of my colleagues asked the supplier how this was measured: It was the pulse train to the stepper motor that was recorded when there was no rotor attached.
I would remind you to look at the role of the supplier a few lines above, especially where it mentions "meaningful specifications." How many of you centrifuge samples without a rotor? Not many I'm guessing. This simple instrument had a specification that was absolute rubbish, but what about more complex ones? Spectrometers are delicate instruments and are made by instrument companies that are based on engineering. Engineers love specifications, for everything-until the marketing department gets their hands on them. The key issue is that you need to understand how the specification was measured and not take it at face value.
Here's where we get to the Clint Eastwood approach to risk management: Are you feeling lucky? User requirements for commercially available instruments are expected to be minimal. But requirements must also be testable in the OQ using calibrated instruments and traceable reference standards according to the updated version of USP <1058> (4). As mentioned above, minimal does not mean nothing. We also need our instrument specifications to be scientifically sound and by coincidence so does the U.S. Food and Drug Administration (FDA)! If you look at 21 CFR 211.160(b) in the GMP regulations you'll also see the phrase "scientifically sound" applied to anything we do in the laboratory (2). Scary stuff, eh?
Let's assume that we want to purchase an ultraviolet–visible (UV–vis) spectrophotometer. There are many available that come in a range of specifications and budgets. Looking at a high-end instrument, we could have one that can operate over a wavelength range between 175 nm and 900 nm-wow! Imagine the glory of having such a shiny new UV–vis instrument. Hang on a minute. Are you really going to measure down to 175 nm (not forgetting the nitrogen purge)? Step back and ask the following questions: Although the instrument specification is wide, what are you actually going to use the instrument for? What is a realistic wavelength range for your work? Many laboratories may only use a UV–vis instrument over a far narrower range, say between 220 nm and 290 nm.
If you remember the ISO 17025 discussion earlier in this column, the laboratory specification is 220–290 nm, compared to the instrument specification of 175–900 nm. The former is what you need in your URS, and simply copying the supplier's specification will lead you into scientific and regulatory trouble. Think about what you would have to do about qualifying the wavelength accuracy. Holmium can be used over the range from 240 nm to 640 nm with 14 traceable peaks. But what will you do in the 175–240 nm and 650–900 nm wavelength ranges? The key message is to specify what you will want rather than what the supplier can offer you.
Associated with this message is the "just in case" argument: For example, you might currently work in the range 240–280 nm, but you might want to widen the range someday. How will this future need impact the specification and how you will verify that in the OQ? My suggestion would be to specify what you need now rather than in the future. When your requirements are updated, look at the new requirements and decide what needs to be done, such as update the URS, extend the wavelength range, and so on.
This approach also applies to other parts of the instrument specification; you need to specify what you need rather than what is offered, including specifications such as
This approach has two advantages. The first is to define what you really want and second to avoid purchasing an instrument that you will never use the complete range of functions available.
If you know how you will use the instrument, writing the specification is much easier. Do you want a research instrument for detailed spectroscopic work or a simpler instrument that just measures absorbance of materials at fixed wavelengths? Thus, a minimal specification for the laboratory is based on what you want the instrument to do and not the supplier specification. From the understanding of intended use will flow the actual specifications based on that usage. While you may use the supplier's specification as a basic starting point for your URS, don't slavishly copy the specification but instead understand how each parameter was measured and adapt accordingly for use. Suppliers have a responsibility here to write meaningful specifications to help all users purchase the right instrument for their needs.
However, if we continue to avoid writing specifications because "we know what we want" (but don't write it down) then we will still purchase lemons rather than the right instrument for the right job.
What is the situation if you want to buy the second or third spectrometer of the same make and model? Do you need to write a new specification? Here you should be practical. First, review the current URS for the instrument and ask yourself the following questions:
Inertia and fear of the unknown are the factors that stop analytical scientists from writing specification for their instruments. There is also the attitude of management-why waste time, just buy the instrument?
Although we have discussed quality standards, GxP regulations, and the need to specify your instrument correctly to meet them, the bottom line is less about interpreting clauses in regulations and standards and more about buying the right instrument for the right job. It is investment protection: Resources are scarce and you must spend money wisely. Get the specification right for business reasons and compliance comes as a bonus. You know it makes sense, but does management?
I would like to thank Paul Smith for his constructive comments during the preparation of this column.
(1) International Organization for Standardization (ISO) 17025, "General Requirements for the Competence of Testing and Calibration Laboratories," (International Standard Organisation, Geneva, Switzerland, 2017).
(2) Code of Federal Regulations (CFR), 21 CFR 211, "Current Good Manufacturing Practice for Finished Pharmaceutical Products" (Food and Drug Administration, Silver Spring, Maryland, 2008).
(3) Code of Federal Regulations (CFR), 21 CFR 58, "Good Laboratory Practice Regulations for Non-Clinical Laboratory Studies," (Food and Drug Administration, Silver Spring, Maryland, 1978).
(4) General Chapter <1058>, "Analytical Instrument Qualification," in United States Pharmacopeia 40, 1st Supplement (United States Pharmacopeial Convention, Rockville, Maryland, 2017).
(5) R.D. McDowall, Spectroscopy 32(9), 24–30 (2017).
(6) European Commission Health and Consumers Directorate-General, EudraLex: The Rules Governing Medicinal Products in the European Union. Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use. Annex 15: Qualification and Validation (Brussels, Belgium, 2015).
R.D. McDowall is the director of R.D. McDowall Limited and the editor of the "Questions of Quality" column for LCGC Europe, Spectroscopy's sister magazine. Direct orrespondence to: SpectroscopyEdit@UBM.com