Tag Archives: drug product testing

Dissolution Testing and Development

November 27, 2023 Bob Brousseau

An Introduction to Dissolution Testing and Development

Dissolution testing is the monitoring of drug substances in a controlled environment from a solid dosage form (i.e., capsules, tablets) to a solution state. These “tests to characterize the dissolution behavior of the dosage form, …also take disintegration characteristics into consideration, are usually conducted using methods and apparatus that have been standardized virtually worldwide over the past decade or so, as part of the ongoing effort to harmonize pharmaceutical manufacturing and quality control on a global basis.”¹

Devising a Strategy
When devising a dissolution testing strategy, “a simple but broadly applicable analytical method is always desired.”² Dissolution analysis is generally performed via UHPLC for faster sample analysis due to the number of samples required. Creating an analytical method should incorporate guidelines from The European Medicines Agency’s (EMA) International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), which are also interchangeable with the FDA. These are designed to “avoid redundant testing by (the) industry.”³

It’s the Media…
Dissolution testing is designed to mimic conditions found in the human stomach. As these conditions vary widely from patient to patient, so too should the testing environment. The ranges for the media should allow for various pH levels. These sets should be notated and designed to simulate FaSSGF (fasted state simulated gastric fluid), FeSSIF (fed state simulated intestinal fluid), and FaSSIF (fasted state simulated intestinal fluid). Compendial media is generally HCl or sometimes acetate or phosphate pharmacopeial buffers. As mentioned, with this many simulated environments, along with multiple time sets/points, there will be many samples necessary, and analysis by UHPLC is optimal for timely turnarounds.

We Can Assist with your Dissolution Testing and Development Needs

AMPAC Analytical has years of experience and numerous experts in dissolution testing. We can support release testing, stability, method development, and assist with formulation development through dissolution analysis. We utilize paddle and basket apparatuses in the dissolution phase of testing. Additionally, our equipment offerings include Agilent Infinity II and Thermo Fisher Vanquish Horizon UHPLCs. Please contact us with any specific questions or to receive a quote for your drug product dissolution testing and development needs.

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Some Background and Concerns About PFAS

November 12, 2023 Bob Brousseau

The Background and Concerns of PFAS

(Per- and) PolyFluoroAlkyl Substances (PFAS) are a class of ubiquitous chemicals that have been found in water, air, fish, and soil across the nation and worldwide. Known as “Forever Chemicals,” there are thousands of different PFAS, and they are present in consumer, commercial, and industrial products.¹ Having one of the strongest bonds in organic chemistry, their structures proved to be resistant to heat, water, oil, and degradation.² They are found in “food packaging and non-stick cookware, cosmetics, waterproof and stain-proof textiles and carpet, aqueous film forming foam (AFFF) to fight Class B fires, and as part of metal plating processes.”³ Teflon and Scotchgard were two of the pioneering products to utilize these fluoropolymers. The two most common PFAS are perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS).

Health Concerns of PFAS

Some of the most frequently cited health concerns associated with PFAS include adverse cardiovascular, immunity, developmental, and hepatic effects.³,⁴The most commonly heard refrain to minimize these concerns is that if they are so prevalent, why are there
not more health issues associated with them? In fact, “The Lancet Commission on Pollution and Health reported that pollution was responsible for 9 million premature deaths in 2015, making it the world’s largest environmental risk factor for disease and
premature death.” This was updated in 2019, and those numbers held steady, accounting for one in six deaths worldwide.⁵/i> While this number includes all types of pollution, the impacts are clear.

The Exposure Concerns of PFAS Are Regulatory and Legal

Due to their combination of persistence, pervasiveness, mobility, and the ability of some to bioaccumulate (or build up in animals and humans), they have been in the news recently too.⁶ Predictably, they are also now moving through the courts.^7-9 Some of the most common areas of litigation are directed at PFAS found in drinking water and firefighting foam. The regulatory initiatives are also increasing. These address a range from water and soil to numerous manmade products including food packaging.^10,11 The European Chemicals Agency (ECHA) and the NIH have a wealth of guidance and regulations that apply to PFAS.^12,13

PFAS Detection

The EPA has useful direction for analytical methods development and sampling research that outlines the “laboratory validation process following a particular rulemaking or guidance effort and are available to support regulatory or guidance activities.”¹⁴ For
technique and equipment, PFAS are typically analyzed by mass spectrometry, coupled with gas chromatography or liquid chromatography (GCMS and LCMS), which enables detection in the low parts per billion.

AMPAC Analytical has years of experience and numerous experts in trace analysis by mass spectrometry who can assist with method development for high-volume analyses for both common and atypical sample matrices that will allow you to stay ahead of evolving regulatory concerns. Please contact us with specific questions or to receive a quote for PFAS quantitation.

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General Information and Guidance
o Per- and Polyfluoroalkyl Substances (PFAS) | US EPA
o PFAS Explained | US EPA
o Perfluoroalkyls | Toxicological Profile | ATSDR (cdc.gov)
o Key EPA Actions to Address PFAS | US EPA
Health Concerns
o Exposures to Per-and Polyfluoroalkyl Substances (PFAS): Potential Risks to Reproductive and Children’s Health – ScienceDirect
Regulations
o PFAS Regulations: Past and Present and Their Impact on Fluoropolymers | Perfluoroalkyl Substances | Books Gateway | Royal Society of Chemistry (rsc.org)

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Gas Chromatography – An Introduction

October 30, 2023 Bob Brousseau

A Brief History of Gas Chromatography
Gas chromatography (GC) is one of the most important and prevalent analytical tools available to chemists. It was invented in 1952 by A.T. James and A.J.P. Martin as an outgrowth of research dating back to the previous decade.^1-6 Their early techniques on adsorption and partition enabled some of the later developments that A.J.P. Martin spoke about at the 1957 Lansing Symposium, entitled, “Past, Present and Future of Gas Chromatography.” He concluded his address with the following prediction: “If we tie the gas chromatograph to other pieces of laboratory equipment, we have the possibility of almost the automatic chemist…”² While the idea of an “automatic chemist” hasn’t quite come to fruition, Martin’s belief “that the uniting instrument of the gas chromatograph in the center” of his lab of the future certainly has.² With the meteoric rise of GC⁷, its adoption and adaptation continued unabated in the ensuing decades. Then, “The introduction of robust, efficient, and reproducible fused-silica capillary columns and the provision of relatively inexpensive but reliable equipment for GC-MS provided a crucial new impetus in the 1980s.”¹ Interestingly, the GC column saw some major advancements within just a few miles of AMPAC Analytical Laboratories. At that location, Walter Jennings and the company he co-founded, J&W Scientific, were instrumental in the development and manufacturing of capillary GC columns. The company was eventually purchased by Agilent in 2001.^8,9

GC Capabilities
Some of the analyses that GC can do include the separation of compounds in mixtures based on the polarity of the compounds, testing for purity – or for impurities, e.g., and detection of residual solvents. Conversely, with a technique known as preparative chromatography, GC can be used to prepare pure compounds from a mixture. In pharmaceutical analysis, there are additional applications:

Analysis of various functional groups.
Determining purity of pharmaceutical compounds.
Analysis of drugs that are commonly abused.
Determination in pharmaceutical R & D the identity of natural products that contain complex mixtures of similar compounds.
Use in metabolomics studies.10

GC for Testing Residual Solvents
The testing of residual solvents is necessary to ensure potency and, with some solvents, to determine their potential negative effects. GC is an excellent choice to do this. Residual solvents are separated into three classifications by the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use):

Class 1 solvents: Solvents to be avoided – Known human carcinogens, strongly suspected human carcinogens and environmental hazards. The Permissible Daily Exposure (PDE) of these solvents used in pharmaceutical products can range from 2 to 1500 parts per million (PPM).

Class 2 solvents: Solvents to be limited – Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity and solvents suspected of other significant but reversible toxicities. The PDE for these solvents ranges from 50 to 3880 ppm.

Class 3 solvents: Solvents with low toxic potential – low toxic potential to man requiring no health-based exposure limit. Class 3 solvents have PDEs of 50 mg or more per day.¹¹

Within these three classifications, some of the most commonly used solvents are listed:

Benzene (class 1)
Acetonitrile, Cyclohexane, Hexane, and Methanol (class 2)
Acetic Acid, Acetone, and Heptane (class 3).^11,12

Headspace GC (HSGC) and Direct Injection GC
In addition to the numerous GC developments such as column type, phase and coating techniques, and multidimensional GC, two types of sampling methods arose: direct injection (“DI”) and headspace (“HSGC”). In the former, the sample is injected “directly” into a typical sample injector of the GC column. In HSGC, when heated, “the more volatile compounds will tend to move into the gas phase (or headspace) sample. The more volatile the compound, the more concentrated it will be in the headspace. Conversely, the less volatile (and more GC-unfriendly) components that represent the bulk of the sample will tend to remain in the liquid phase.“¹³

Therefore, by extracting the “headspace vapor and injecting it into a gas chromatograph, there will be far less of the less-volatile material entering the GC column, making the chromatography much cleaner, easier, and faster.”¹³ Generally, HSGS is much cleaner and results in less wear on the column. For more on comparative techniques with DI and HSGC, please see the first entry in the “Resources” section below.

We Can Assist with your GC Needs

AMPAC Analytical has years of experience and numerous experts in Gas Chromatography who can assist with method development for analyses for both common and atypical sample matrices that will allow you to stay ahead of evolving regulatory concerns. Please contact us with any specific questions or to receive a quote for your GC needs.

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Resources

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Chiral Purity Analysis – The Need to Know What Both Hands Are Doing

October 10, 2023 Bob Brousseau

Background on Chiral Purity
Chirality refers to the phenomenon that occurs when a mirror image cannot be superimposed. It is sometimes called “optical rotation”.

The origin is from the late 19th-century Greek word kheir (‘hand’) and is one of the easiest demonstrations of the concept. Although a person’s hands may appear virtually identical, if they were switched, the outcome would be very different. Amino acids and sugars are the chiral building blocks of larger molecules such as peptides, proteins, and nucleic acids. Therefore, those polymers, in turn, are chiral as well.¹ Molecules with chiral centers may have a different therapeutic impact, and this guides the need to test and control chiral purity. The effects of chiral impurities can result in horrific outcomes, as evidenced by the infamous birth defects associated with Thalidomide² or as benign as Aspartame and sugars (the D/L sugars) that, when superimposed, can create different taste sensations (sweet versus sour, etc.) or metabolic activity. Each chiral center can generate two enantiomers. “Enantiomers or optical isomers are chiral molecules which are non-superimposable mirror images of each other,”³ and multiple chiral centers can generate diastereomers (non-mirror image isomers).

Determining Purity
HPLC has been the primary technique for determining chiral purity, with gas chromatography used occasionally. Measurement of optical rotation is a legacy technique that is fast but not as accurate. Historically, HPLC methods used under normal phase conditions could limit the type of molecules that could be analyzed. However, now modern chiral columns are compatible with reverse phase conditions.

Simulated Moving Bed (SMB) Chromatography as an Option for Chiral Purity Analysis
Do you have a partner for chiral separations? AMPAC Analytical has the expertise in performing chiral purity testing, along with the equipment and techniques. Additionally, our parent company, AMPAC Fine Chemicals, has decades of experience conducting chromatographic separations at a commercial scale in a highly regulated environment. Our services include SMB screening, method development, proof-of-concept demonstration, and production. We operate the largest CGMP Simulated Moving Bed (SMB) chromatography unit in the United States. These technologies and expertise are part of a one-stop shop (from 10-millimeter columns up to 1000mm). Our SMB processes can be developed in a few weeks and are easily scalable. In many cases, scale-up from gram to multi-ton quantities can be achieved in fewer than six months. Our facilities include kilo-scale and pilot-scale units to support smaller quantities, also under CGMP conditions. The SMB facilities have been inspected and approved by the FDA for the manufacturing of APIs. AFC has registered four products with regulatory authorities (FDA/EMA) using SMB technology. Along with chiral separations, we can also perform the separation of diastereomers & regioisomers.

Contact us today for information on how we can assist with your raw material, amino acid, drug product, and API chiral purity testing or to learn more about our SMB processes.

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