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Unpacking USP 922 and Water Activity’s Role in the Pharmaceutical Industry
Webinar - March 30, 2021

Unpacking USP 922 and Water Activity’s Role in the Pharmaceutical Industry

In recent decades, scientists and industry leaders have begun taking note of the influence that water activity (also known as aw, RH, or relative humidity) has on chemical stability, microbial stability, flow properties, compaction, hardness, and dissolution rates of dosage forms. With water activity’s greater popularity has come new regulation. The latest related regulation — USP’s General Chapter 922 Water Activity — has been finalized and will be published in May 2021. 

In this live webinar and Q&A, Dr. Tony Cundell, a member of the USP Microbiology Expert Committee that crafted USP <922>, will:

  • Break down the details and implications of the USP’s involvement in water activity regulation and guidelines – specifically the upcoming General Chapter <922>
  • Respond to audience questions related to water activity, its applications, and the USP’s intent behind chapters <1112> and <922>
  • Outline a foundation for how and why water activity is a versatile and valuable measurement
  • Explain the role of water activity in the mitigation of the risk of microbial contamination in non-sterile drug products
  • Explain why the USP has chosen to emphasize water activity and broaden the need to measure it

See below the video for a full transcript.

About the presenter

Dr. Tony Cundell is a member of the current USP Microbiology Committee of Experts, the Joint Committee that developed USP <922> Water Activity. He takes a leadership role in the area of modern microbiology methods. 

Dr. Cundell consults with pharmaceutical, consumer health and dietary supplement companies, microbiology instrument manufacturers, contract testing labs and sterile compounding pharmacies in the areas of microbial risk assessment, regulatory affairs, and microbiological testing. 

He was also co-chair of the PDA task force responsible for 2014 Technical Report No. 67 Exclusion of Objectionable Microorganisms from Non-Sterile Drug Products.

Webinar and Q&A transcript

Intro and overview

Thanks very much Rita Peters for that introduction. My name is Tony Cundell, and my topic today is the USP Role in the Promotion of Water Activity Determination in the Pharmaceutical Industry.

First, a few disclaimers. I am an independent consulting microbiologist to the pharmaceutical industry. I’m not an analytical chemist so my emphasis will be on microbiology today. I am a member, as Rita said, of the 2020/25 USP Microbiology Expert Committee. My presentation today is my opinions and not necessarily those of the U.S Pharmacopeia or my industrial clients.

So this is an overview of my presentation. I’ll make a brief introduction to water activity. I’ll discuss the concept of hurdle technology as applied to drug products. I’ll discuss the role of water activity and mitigating the risk of microbial contaminations and non-sterile drug products. And I’ll discuss the active duties of the USP committee in this particular area.

What is water activity?

First, a little whimsy. This is the planet earth which is a wet planet, and because of the water on earth, our planet teams with life. 

In contrast, Mars is considered a dry planet. So it’s inhospitable to life. And yes, this is a photograph of the actor Matt Damon who appeared in the science fiction movie, The Martian.

So what is water activity? Water activity, or equilibrium relative humidity, measures the vapor pressure generated by the moisture present in a hygroscopic product. 

Water activity equals the ratio of P divided by P zero where P is the partial pressure of the water vapor at the surface of the product and P sub zero is the partial pressure of water vapor above pure water at a specified temperature. 

So water activity reflects the active part of the moisture content or the part, which can be exchanged between the product and the environment. Water activity is a unitless ratio and it ranges from 1.0 for pure water to 0.0 for a bone dry material.

 

Water activity applications

What are some of the applications of water activity determination in the pharmaceutical industry? 

  • It can determine the level of thermodynamic control for desired solid forms, so the production of the hydrate version and anhydrite. 
  • It can be used for selecting excipients where the water activity may impact the material flow, compression characteristics, hardness, and dissolution of the solid dosage form. 
  • You can reuse water activity in optimizing fluidized bed drying processes. 
  • You can reduce the degradation of active ingredients within product formulations by controlling the water, and this is especially important to those in active ingredients that are susceptible to chemical hydrolysis. 
  • Water activity can be used to establish the level of protection to product formulations to moisture by the primary packaging material during their shelf life
  • It can be used as a complementary method to the Karl Fisher titration for monitoring chain changes in water content. So if you construct a water absorption isotherm and show the relationship between the Karl Fisher titration for water content and the water activity, you can do the simpler measurement of water activity to determine the water content. 
  • In the area of microbiology, you can optimize formulations to improve the anti-microbial effectiveness of preservative systems. By controlling water activity, you can reduce the susceptibility of formulations to microbial contamination. 
  • You can use water activity as a stability test parameter to confirm that the packaging protects a drug product from moisture and maintains the microbiological stability of the product
  • You can use water activity as a tool to justify the reduction of microbial testing of different non-sterile formulations.

 

Water activity and hurdle technology

So next I’ll discuss hurdle technology. 

You might ask, “What is hurdle technology?” Well, it’s a concept that was developed in the food industry, and it can be applied to drug products. 

Hurdle technology deliberately combines existing and new preservation techniques to establish a series of preservative factors, so-called hurdles, that the microorganisms in question are unable to overcome, jump over. These hurdles may be storage, temperature, water activity, acidity and alkalinity, redox potential, anti-microbial preservatives. And at the bottom of the slide, I have the reference to the pioneering publication on hurdle technology for food products.

 

Water activity and microbial risk analysis

Next, I want to discuss microbial risk analysis for drug substances and drug products. So the questions you ask when you do a risk assessment are: 

  • What is the water activity of the material?
  • Is water used in the final steps of chemical analysis in isolation of the drug substance or active pharmaceutical ingredients? 
  • Does the manufacturing process increase, reduce, or eliminate bio burden? 
  • Does the manufacturing environment and process contribute to microbial contamination? 
  • Does the manufacturing side have a good history of microbial control? 
  • Certainly, with drug products, a key question is the water activity of the product. 

Also, you would consider the microbial quality of the pharmaceutical excipients, the manufacturing process environment, the testing history, the packaging that protects the product, whether it’s a multi or single use product, and what is the medical status of the recipient of the product.

Next I want to discuss the role of water activity in the mitigation of the risk of microbial contamination in non-sterile drug products. 

Water activity has been extensively used in the food industry to prepare products with low risk of microbial contamination, and also to extend the shelf life of the products. This use of water activity goes back to 1000 BC in China where drying, smoking, salting and spicing was used for food preservation. 

Water activity can be successfully employed and the cosmetic consumer products and pharmaceutical industries as well as the food industry. 

Here are some of my favorite low water activity foods: pickles, sausages, smoked salmon, and jams.

 

Water activity and microbial growth

Where did the linkage between water and activity and microbial growth come from? Well, the Australian microbiologist, Bill Scott, in the early ’50s showed that microorganisms have a limiting water activity level below which they will not grow. Water activity, and not water content, determines the lower limit of available water for microbial growth. And here at the bottom of the slide are the references to his pioneering papers. 

So what generalizations can we make about water activity in microbial growth? All microorganisms have minimum and optimal water activity requirement for growth. Drug products with water activity below this requirement will be self-preserving or microbiologically stable, and these findings can be used in microbial risk assessment and the establishment of microbial specifications and testing programs.

This particular slide shows the water activity requirements for different types of organisms. 

 

Wet vs dry products

At high water activities of above 0.95, bacteria out-compete yeast and molds. Below 0.85, most bacteria do not grow. Below 0.75 most yeast and molds don’t grow. Between 0.75 and 0.60, only highly specialized microorganisms not usually found in pharmaceutical products will grow. This could be microorganisms in the dead sea. And below 0.6, no microorganism will grow. So this gives us a lot of opportunity to control microbial growth. 

Here is the water activity requirements of a range of well-known microorganisms. On the left of this is bacteria on the right, mold and yeast. As I said, gram-negative organisms have the highest requirement for water activity. Gram-positive organisms, a lower requirement and Staphylococcus aureus does not grow below 0.86, and the same pattern is seen with yeast and molds.

There is a small group of highly specialized organisms, halophilic bacteria, osmophilic yeast and xerophilic fungi that will grow at water activities approaching 0.6, but they grow very slowly. So this lends itself to a division between wet and dry products. A high water activity – above 0.8 – represents a moist system and a low water activity – below 0.7 – represents a dry system. You should be aware that if you expose a high water activity product to low humidity, you will lose water, and conversely, if you expose a low water activity to a high humidity, the product will gain water. So this gives a division between low and high risk products based on water activity.

 

Water activity and dosage forms

So in the low risk, we have things like ophthalmic ointments, tropical ointments, liquid filled capsules, liquid centered cough drops, powder filled capsules, compressed tablets, suppositories and inhalation aerosols. High risk products would include nasal sprays, inhalation solutions, rectal creams, liquid antacids, eyedrops, oral liquids, tropical lotions, cough syrups, oral canker sore gels, and oral analgesic suspensions. Quite conveniently, products segregate out into a low risk or low water activity products and a high risk and high water activity products.

 

USP 922 and USP’s involvement in water activity

Next I want to discuss the USP involvement in the area of water activity, especially chapters 1112 and 922. 

Just a little background – the U.S. Pharmacopeia has test chapters numbered between one and 999 and they contain general test chapters. It may be cited in an ingredient or product from monographs. So in other words, if your monograph for a particular material has a specification, it will have a counterpart with a test that is described as a general test chapter. In contrast, USP chapters numbered between 1000 and 1,999 are general information chapters that provide broad guidance, but are not binding. These chapters are not GMPs. GMPs are derived from the government regulations and FDA guidance documents.

First I want to discuss the development of 1112. I can take some credit here. Bob Friedel and myself co-authored a stimuli article that was published in a pharmaceutical forum in 1998 and it was entitled The Application of Water Activity Measurement to the Microbial Attributes Testing of Non-Sterile Over the Counter Drug Products. And yeah, I was reminded that this is many years ago. 

So the USP published a general information chapter in the Pharmacopeial Forum on in November-December of 2002 and this was entitled 1112 Application of Water Activity Determinations to Non-Sterile Pharmaceutical Products.

The chapter became official in the second supplement to USP 29 on August of 2006. So it’s been in the USP for some time. However, it was the development of USP <922> water activity, the microbiology expert committee is revising <1112> to focus on the microbiology aspects of the chapter. 

So what’s the difference between the two chapters? <1112> is a general information chapter, provides guidance. It’s focused on risk assessment for microbial growth, describes basic calibration of instruments and salt solution. At the time when we wrote this chapter we found the dew point chilled-mirror instrumentation had been published as an official method in the AOAC international so we referenced that particular method.

It does not discuss a wide range of instrumentation and it does define water activity and how it can be applied to the non-sterile drug products and microbial testing. In contrast, <922> is a general test chapter and it’s focus on water activity test methods for all types of drug products. It contains recommendations and requirements for instrument qualification, calibration, and measurement, and it describes the types of instruments that can be used and the pros and cons and lists their possible use. And it defines water activity and includes additional information about how the measurement works and what affects the result of the measurement. So you can see the different intent of the two chapters. Again, these are some of the applications of water activity that I discussed earlier.

So what was the evolution of this particular chapter? It was first published in the Pharmacopeial forum in November-December of 2018 as an in-process revision with stakeholder comments. And based on public comments that were received, it was rewritten and we significantly improved the chapter based on the comments and it was published in the Pharmacopeial Forum in January-February, 2020. So the proposed new chapters outline the recommended concrete methods to qualify, calibrate and use water activity meters to accurately measure water activity in raw materials and products.

It is a little unusual compared to other general test methods because it discussed water activity broadly and recommends a number of measurement technologies, not just one. So this is the table of contents of the chapter. It has an introduction, theoretical background factors affecting water activity, the application of water activity measurements, types of water activity instruments, qualification of these meters, operation and calibration of the meters, procedures for verification and validation, and a section on the operation calibration and validation of NIR instruments and it has three references.

So the four major types of instruments discussed were dew point temperature chilled mirror instruments, two types of electronic hygrometers, and tunable diode laser technology. And it does discuss the NIR spectrometry. I won’t go into details of these technologies. As I said, I’m merely a microbiologist, not an analytical chemist, but I will say the user should select the instrument based on their use. So you have to consider the level of accuracy and precision that you would require, and typically microbiologists are interested in lower level of accuracy and precision where chemists favor a high level of accuracy and precision. You consider the throughput of samples, whether the measurement is affected by some attributes of products like containing volatile materials, whether you want to take a sample or do a measurement inside a container. So you have to consider what use you’re going to put the instrument to and make a decision on what would be the best instrument for your particular lab.

One area that was not discussed in <1112> was sample preparation. So <922> emphasizes that during transportation from the lab, samples need to be kept in well sealed water impermeable containers to protect them from any change in water composition due to exposure to different temperature and humidity in the sampling site in the lab. And also it’s recommended the sample container have a minimal headspace to avoid a significant change in water activity due to re-equilibration of the sample to the environment in the sample container. Also, it discussed the sample measurement and calibration checks or performance checks should be performed every day the instrument is used to perform measurements. And also you should verify that the instrument is not due for its periodic calibration prior to forming a measurement.

So you recall the equilibrium water activity and the equilibrium temperature and report the value or the mean value of replicant measurements. Typically, you report to two or more significant digits depending on your application, and you report the temperature rounded to the nearest 0.1 degree, because water activity does change slightly with temperature of measurement.

The sample presentation may be important. The user manual will tell you how much material should be in the sample chamber. You also have some options in terms of sample preparation and how the sample is presented in the instrument. For example, a compressed tablet could be presented as whole units or a ground tablet. Chewable gels could be sliced into thin pieces and capsules could be presented as whole units or the capsule content. And based on these presentations, you may see slight differences in the water activity measurement.

Instrument classification. The USP has an excellent chapter <1058> Analytical Instrument Qualification. It categorizes lab instruments into Group A, B, and C. Group A, which I don’t describe here, are trivial devices that are used in the lab like mixers or stirrers. Group B instruments, a typical example is a pH meter on an oven and this group only require routine calibration maintenance and a performance check. And the extent of these activities may depend on the criticality of the application. And also these instruments may have firmware, but not software that is updated or changed by the user. Group C instruments comprise of analytical instruments with a greater complexity and significant degree of computerization such as high pressure liquid chromatographs and mass spectrometers and all elements of qualification including software validation must be considered to ensure the proper functioning of instruments in this group. But the take-home message is most of these meters fit into Group B, so you can use a USP <1058> as a guidance document.

I’ve basically covered this slide. In contrast to Group B instruments, there may be more requirements with NIR instruments and this is discussed in USP <856>.

Calibration checks, or performance checks, are typically done each day you use the instrument. So saturated salt solutions may be prepared in a sample cup or prepared in a separate container and transferred to a sample cup for use. And you would use this material according to the recommendations of the instrument manufacturer in regard to the amount of sample that will be present in the measurement chamber. So in addition to the saturated salt solutions listed in <922> Table 1, purified water may be used as a 1.00 water activity standard solution, but it’s not required to include a standard for zero water activity. And it’s acceptable to use in appropriate low water activity standards such as lithium bromide or lithium chloride.

So the procedure for standard solutions is that the instruments should be calibrated either using a prepared or purchased solution or even using a calibrated humidity generator while prepared solutions use reference Table 1.

When do you calibrate? You would do that at least annually, anytime that the calibration check or performance check fails, and anytime you change the range of intended use. And you would calibrate as instructed by the manufacturer, you would calibrate at the temperature views where it’s feasible. You would bracket the sample. Well, if you have a large range, you might also have a midpoint sample.

So in terms of performance check, it’s a bit like — to an unsophisticated microbiologist — like a pH meter. Here are the saturated salt solutions and they range from high water activity to low water activity. And in the right hand column, there is the value and the precision you would expect for measurements at 25 degrees. So I did mention that there are references in the chapter and I was honored that the book that I edited with an Anthony Fontana, Water Activity Applications in the Pharmaceutical Industry were included plus two excellent standard references to water activity measurements.

I just want to take a minute to give a shout out for people who are involved in stability programs. Water activity is an excellent tool to measure the protection of the product by the primary packaging material. I was involved, this is a war story. The company I worked for marketed an oral contraceptive in a blister pack in a South Indian nation. And this particular product failed, the woman taking the oral contraceptives became pregnant. And what we found was the blister packaging by material differs in the moisture transmission, and the transmission rate was high enough and in a very high humid area for the water to penetrate the packaging and accelerate the chemical hydrolysis and degradation of the active ingredient. So this is a great tool.

 

USP’s future with water activity

So what are the USP plans in the area of water activity? Stakeholders’ comments on the revised chapter <922> had been received and reviewed, and if you worked for a company that made submissions to the USP, that certainly made our work easier and resulted in a much better chapter. So where appropriate, additional revisions were made to chapter <922>. The chapter was approved by ballot by the Physical Assay expert committee and I’m pleased to announce that it will be published as official in May 2021, in a couple of months. And in response to this publication, the USP microbiology expert committee will remove the theoretical background and details of analytical methods from <1112> and site the chapter <922> and focus on microbial risk analysis.

 

Conclusion

So in conclusion, I believe the USP has provided an important analytical tool with water activity measurement to help develop better non-sterile drug products. I will thank my colleague Martin Coffey from Bausch & Lomb for the use of a couple of slides from a future presentation, and I’ll take questions as time allows. Thanks very much for your attention and I give it back to you Rita.

 

Q&A session

How is water activity used to help support skip-lot testing for non-sterile products?

To be frank, I’m a big fan of skip-lot testing. In my experience working in product development, I would recommend that you do a risk assessment and decide what risk of microbial contamination your product has. So a compressed tablet, for example, has a very low risk of microbial contamination. So write up your risk assessment, and in the submission to the FDA, suggest that a microbial specification is not required, so then does not become a specification. And if you have a controlled process, you control your water system, your ingredients, your manufacturing process, you should consistently get a low water activity, low bi-burden product and skip-lot testing would not be necessary.

What are your thoughts on using water activity measurements to replace Karl Fischer titrations?

Well, as a microbiologist, colleagues have complained about the smells that might come out of incubators in the microbiology lab. The Karl Fischer measurement uses pyridine which is an unpleasant solvent, and it’s a relatively complicated assay. So water activity measurements could be substituted for water content measurements. 

But I would even go further. And in many cases, the critical parameter is not water content, it’s water activity, and maybe you should file the specification for water activity for that particular product and not water content.

The only downside is you have to construct water absorption isotherms for each product so that you can use water activity to derive a water content measurement. I hope chemists listening to that today believe that I’ve got it right.

If water activity data is very low, say 0.6, can we justify removing the micro testing?

Yes. If the product is protected by the packaging material, it won’t change during the shelf life. And water activity will be a conservative part, so if you use the same formulation and manufacturing process, you should consistently get a product that will have a low water activity and no organism will grow at that particular level. So the product will have microbial stability. So yes, I think you can make that decision.

What kind of water migration from capsules to powder should be expected in lower moisture environments and what would be a comfortable range to observe?

Yeah. So I did mention water will migrate from a product to the environment depending on the relative humidity and water activity of the product. So I’m not an expert on moisture migration, but obviously the primary packaging material will protect the product during the shelf life. And if the pharmacist dispenses the capsule, they usually only give you a 30 day supply and the packaging that they use will continue to protect the product. So I really haven’t answered the question. So my feeling is the emphasis should be on product protection.

What’s the difference between water activity and moisture content and when should each be used?

Well, it’s an energy situation and the water content could be chemically locked up in the product but still measurable. The water activity measures water that is free water. I know water activity experts don’t like it to be described as free water, but it’s water that can migrate from the product and the environment, and in lots of cases, that is the driver for the parameters that you’re interested in whether it will be blow of the powder, chemical degradation of an active ingredient or sufficient water to support the growth of organisms.

So I wouldn’t suggest in many cases in formulation development, the formulators in the camera should determine whether it’s water content or water activity which is going to be the critical parameter and make a decision on what one to use.

Of the major types of water activity instruments, is there one type you found to be most reliable and/or valuable?

I find there’s tremendous merit in all of them. I have to admit when I got started in this particular area, I did use the Dew Point Chilled Mirror instrumentation and I did find it was robust. But some of these electronic devices are much more suitable in process control or testing powdered material. 

So I’m going to punt on this one and say, you need to evaluate how you’re going to use these instruments and make a decision on which one you would use. In my experience, they are all quite reliable, but there are differences in accuracy and precision and how they’re used, and also cost. So you need to decide which one would be best for your purpose.