Tag Archives: method development

Nitrosamines – An Update

August 29, 2023 Bob Brousseau

NDMA

The linkage between nitrosamines and cancer was first postulated by William Lijinsky in 1970. Then, in 2018, N-nitroso-dimethylamine (NDMA)) was detected in an active pharmaceutical ingredient, Valsartan (an Angiotensin-II-receptor antagonist). Finally, the FDA issued a guidance for the industry, “Control of Nitrosamine Impurities in Human Drugs”, in the fall of 2020. However, the guidelines continue to evolve. There has been an update in March of 2021, with ongoing risk assessments. Other regulatory agencies have instituted their own, along with updates. For example, since our blog series on nitrosamines, there have been some regulatory updates from the European Medicines Agency (EMA). Their new guidelines are outlined in a document entitled, “Questions and Answers for Marketing Authorization Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 Referral on Nitrosamine Impurities in Human Medicinal Products.”1 The updated section answers the crucial question, “Which limits apply for nitrosamines in medicinal products?”

The answers are provided with a definition of nitrosamines and acceptable exposures:

“The ICH M7(R1) guideline defines N-nitrosamines as substances of the “cohort of concern” for which limits in medicinal products refer to the so-called substance-specific acceptable intake (AI) (the Threshold of Toxicological Concern, TTC, value of 1.5 ug/day cannot be routinely applied) which is associated with a negligible risk (theoretical excess cancer risk of <1 in 100,000 over a lifetime of exposure). The calculation of AI assumes a lifelong daily administration of the maximum daily dose of the medicinal product and is based on the approach outlined in the ICH M7(R1) guideline as well as the principles described in relation to the toxicological evaluation in the assessment report of the CHMP’s Article 5(3) opinion on nitrosamine impurities in human medicinal products.”^1,2 (A previous blog examined TTC, here.)

A Useful List of Nitrosamine Limits

In Appendix 1 found on the EMA site, there is a list of more than eighty nitrosamines listed, along with CAS numbers, known medicinal sources, CPCA (Carcinogenic Potency Categorization Approach) categories, and their guidance publication dates.^3,4

Some Caveats

There are some exceptions that should be considered. For example, the EMA states, “The ‘less than lifetime’ (LTL) approach should not be applied in calculating the limits as described above but can only be considered after consultation with competent authorities as a temporary measure until further measures can be implemented to reduce the contaminant at or below the limits defined above.”¹

Additionally, those medications intended for advanced cancers also have some exceptions. For example, “If the active substance itself is mutagenic or clastogenic at therapeutic concentrations, N-nitrosamine impurities should be controlled at limits for non-mutagenic impurities according to ICH M7(R1).”

There is also guidance when one or more than one nitrosamines may be present. For the latter, the guidance advises one of two approaches:

The total daily intake of all identified N-nitrosamines is not to exceed the AI of the most potent N-nitrosamine identified.

The total risk level calculated for all identified N-nitrosamines is not to exceed 1 in 100,000. The approach chosen needs to be duly justified by the MAH (Marketing Authorization Holder)/Applicant.¹

Final Thoughts on Nitrosamines

Nitrosamine guidance worldwide is ever-evolving, yet the impetus to quantify and regulate them is clear. There will doubtlessly be further updates to regulations. AMPAC Analytical Laboratories – an SK pharmteco company (AAL) is an industry leader in the detection of nitrosamines and other genotoxic impurities (GTI), We have the specialized expertise, equipment, and methodologies to detect these impurities by gas chromatography or high-performance liquid chromatography coupled with mass spectrometry to support your API project. Also, importantly, AAL can assist in navigating those projects within today’s regulatory landscape. Please contact us with any specific questions or to receive a quote for nitrosamines or other GTIs. 

References

Resources

AMPAC  Analytical

Watch Our On-Demand Webinar on Genotoxic Impurities 
https://ampacanalytical.com/events/on-demand-webinar/ 
AMPAC Analytical’s Nitrosamine Impurities Testing Webpage 
https://ampacanalytical.com/laboratory-services/ampac-analytical-offers-ndma-analyses-of-api-and-dp/#1644962917933-ed2cb310-b026

General Information on Nitrosamines 

An Organic Chemist’s Guide to NNitrosamines: Their Structure, Reactivity, and Role as Contaminants 
https://pubs.acs.org/doi/10.1021/acs.joc.0c02774?ref=pdf

Nitrosamine and Pharmaceuticals 

Information about Nitrosamine Impurities in Medications 
https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications 
Prevalence of Nitrosamine Contaminants in Drug Samples: Has the Crisis Been Overcome? 
https://doi.org/10.1002/ardp.202200484 
Nitrosamines Impurities in Pharmaceuticals, the Abrupt Challenges They Bring, and Approaches to Tackle the Risk 
https://doi.org/10.1016/j.xphs.2022.07.016

Critical Analysis of Drug Product Recalls Due to Nitrosamine Impurities 
https://doi.org/10.1021/acs.jmedchem.0c02120 
Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications 
https://doi.org/10.3390/ijerph18189465

Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals
https://doi.org/10.1016/j.xphs.2022.12.022

Blog

Dynamic Vapor Sorption

August 11, 2023 Bob Brousseau

Dynamic Vapor Sorption (DVS) is a gravimetric technique used to measure the change in mass of a material in response to changes to surrounding conditions such as temperature or humidity. DVS is primarily used with water vapor but can be applied to other organic solvents as well for the physicochemical characterization of solids.

DVS was developed by Daryl Williams, the founder of Surface Measurement Systems Ltd., in 1991. The company then delivered the first working DVS instrument to Pfizer in 1992.¹ Since then, many other equipment manufacturers have entered the field.

Figure 1: A DVS isotherm plot indicating sorption and desorption rates and hysteresis. The isotherm shows a typical hysteresis curve where the adsorption phase is almost identical to the desorption phase (i.e. reversible). Note that at 80 %RH, there is net sorption of 0.9% between adsorption and desorption traces. The material appears to be slightly hygroscopic according to the definition in Ph. Eur.²

Sorption, Desorption, Absorption, and Adsorption
There are five main physical processes that occur during the DVS experiment. The first, sorption, is when a material takes on moisture due to increased humidity. Conversely, desorption is the process that occurs when the material loses moisture due to decreasing humidity. Sorption can be classified as one of two types. Adsorption is moisture that is observed on a surface of a material, while absorption is moisture that has penetrated the surface of a material. The fifth term and the term that relates sorption and desorption is called hysteresis. The overall chart that includes and tracks the sorption and desorption rates and hysteresis is called the isotherm. These curves are crucial for understanding the physicochemical characteristics of a solid, such as porosity, polymorphic change, or liquefying of a sample.²

Applications

There are numerous reasons to utilize DVS, and some of the most common within the active pharmaceutical ingredient (API) industry are:

To determine the sorption isotherm;
To evaluate the hygroscopicity of an API powder;
To compare the hygroscopicity of different solid-state forms: solvates, polymorphs, salts, amorphicity, and cocrystals;
To determine the deliquescence point of a material;
To quantify and qualify the amorphous content in drug substance or excipient,³ and
To evaluate packaging materials.

Of course, there are a variety of other applications in other industries, including for building materials, food science, cosmetics, coatings, and sealants.

DVS Analysis of APIs
For pharmaceutical development, DVS is used for a variety of applications, including screening early drug and excipient candidates, establishing processing parameters, and identifying packaging and storage requirements (Figure 2).^4,5

Figure 2: A DVS isotherm of an API showing that the material started to gain significant mass after exposure to relative humidity values of more than 60 %RH. The change here was irreversible, as demonstrated by the desorption curve. DVS could be a useful tool to suggest storage conditions in terms of humidity contents in the surrounding environment.

However, due “to the typically slow establishment of an equilibrium, DVS experiments are rather time-consuming.”⁴ Nevertheless, “water content of solid active pharmaceutical ingredients and excipients, individually and when formulated in pharmaceutical dosage forms, is a parameter that should be monitored throughout the drug lifecycle.”5

As an analytical technique for APIs, DVS has become a necessary step within drug development and production, reducing issues that can arise during manufacturing, packaging, transportation, solubility, dissolution rate, stability, or storage. AMPAC Analytical’s sister company, SK biotek Ireland Analytical Services, has the experience, technology (including a Surface Measurement System’s DVS Resolution Dual Vapor Gravimetric Sorption Analyser), and support, to assist with this vital testing. Both companies are part of SK pharmteco and can easily transfer your project from either business unit to ensure the most optimal solution and logistical support are provided to meet your product timeline. We invite you to contact our team members and discuss how we can assist with your sorption testing requirements.

Figure 3: A SMS DVS instrument like the one located at SK biotek Ireland.

References

https://surfacemeasurementsystems.com/our-story/

Ph. Eur., 2023, 11.2 Edition, Chapter 2.9.39

https://www.sciencedirect.com/science/article/abs/pii/S0022354915303348

https://www.sciencedirect.com/science/article/abs/pii/S0022354918302193

https://www.sciencedirect.com/science/article/abs/pii/S0022354916325230

Blog

Keys To Effective Method Development

July 25, 2023 Bob Brousseau

Effective method development is crucial for the quality control of Active Pharmaceutical Ingredients (API) and Drug Products (DP). Thorough method development enables successful downstream method validation.

The regulatory guidance specifies that:

Method development and validation vary by application (quantitative, qualitative, etc.).
It is phase appropriate.
The client may provide additional guidance/validation criteria.
The validation guidance directs how AMD (analytical method development) is conducted.

Early Adoption of Forced Degradation Analysis
It is recommended that forced degradation be performed early in the method development lifecycle and that method parameters are suitable for mass spectrometry. This will prevent many issues that could occur in later stages and ensures the primary purity method is stability-indicating (specificity). When performing forced degradation, these considerations should be weighed:

Always utilize a control sample without exposure to stressors.
The stressors generally consist of acid, base, peroxide, heat, and photolytic conditions. Other stressors may be used based on known material incompatibility
After exposing the compound to these stressors, target 5-20% degradation of the main peak.
If degradation is not observed under reasonable conditions, then the material can be considered stable under those conditions.

Impurity Genesis and Identification Assessment
Acceptance criteria should be scaled to impurity levels. How can the method unequivocally assess the analyte of interest in the presence of likely impurities, degradants, and the sample matrix? Additional considerations include:

Is the method capable of identifying and/or quantifying a specific compound?
Are there solvents present that can interfere with potential impurities?
Known impurities? Are the known impurities stable under the method conditions?
Is the method specific for degradation byproducts for stability-indicating methods?

Cross-Platform Method Robustness
Robustness refers to a method’s ability to meet its analytical requirements (system suitability requirements) despite small variations of the method’s parameters, such as discrete changes to a column or sample tray temperature, percent organic modifier, flow rate, and detector wavelength. This capability is typically built into the method during method development.

Precision or Accuracy – You Need Both in Strong AMD
AMPAC Analytical development strategy involves the early adoption of forced degradation studies with the goal of every primary purity method being stability-indicating (specificity) and mass spectrometry compatible. The validation strategy is phase-appropriate and application-specific and guides the development strategy. The validation acceptance criteria guidelines are specific to the test methodology, intended use, and level. Finally, method lifecycle performance is assessed, and reevaluation or revalidation can occur.

Blog

Phase-Appropriate Method Development

July 10, 2023 Bob Brousseau

The Cost of Drug Discovery and Development and How to Mitigate It

The path to successful drug discovery and development is extremely long, expensive, and risky and can take between 10 to 15 years at an average cost of more than $1–2 billion for every new drug that is approved for clinical use.1,2 In fact, preclinical drug discovery alone “typically takes five and a half years and accounts for about one-third of the cost of drug development.”3,4 Therefore, even during the earliest stages of a drug product or active pharmaceutical ingredient project, phase-appropriate method development should be instituted to manage costs. This bolsters the chances for success and ensures reliable results, quality management, and reproducibility while avoiding “unreliable results (that) might not only be contested in court but could also lead to unjustified legal consequences for the defendant or to wrong treatment of the patient.”5 At its most basic, phase-appropriate method development maps the “what is needed” to “when it is needed.”6 Effective phase-appropriate method development can provide long-term product support by introducing mass spectrometry compatibility and forced degradation development to ensure your methods are stability-indicating and amenable to unknown impurity identification. By instituting a phase-appropriate method development process, combined with a quality-by-design approach around each logical sequence of events – and rigorously following it – it is more likely to create a cost-effective, successful outcome as you take the drug product through the regulatory process.

It Can Pay to Outsource

As the incentives for strong phase-appropriate method development increase, so too has the recognition of its value. Unfortunately, “it is not uncommon…to find pharmaceutical companies and contract research organizations (CROs) that are not taking advantage of the phase-appropriate approach and simply reference the typical ICH guidance for analytical items, such as method validation.”7 However, while FDA guidance encourages the use of a phase-appropriate approach, it is lacking in details and requirements. This leaves many companies to seek out ICH guidance as an alternative, conservative approach. Also, within their CGMP quality system, they may find it difficult to accommodate differing levels of CGMP compliance throughout the various clinical phases of development. This is when it might be an opportune moment to consider an outside expert that specializes in phase-appropriate method development processes for drug discovery and validation. A successful yet robust phase-appropriate method development program can balance competing interests and requirements and still provide a regimen that meets the overall development goals without sacrificing any of the requirements of the program.

AMPAC Analytical Laboratories (AAL), an SK pharmteco company, has decades of experience in providing a wide array of release testing services for raw materials, intermediates, APIs, and drug products. Our labs are equipped to handle hazardous, cytotoxic/high potency compounds as well as controlled substances for schedule II through V. Additionally, we have not only the expertise to conduct forced degradation experiments but also appropriate instrumentation like mass spectrometers to support later phases of development for your products. Please contact us to discuss how we can ensure the success of your drug discovery and development project and simultaneously reduce risks.

References

Resources