Stability testing for medical Cannabis - What needs to be considered

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Introduction

Stability is defined as the extent to which a product retains, within specified limits, the same properties and characteristics that it possessed at the time of its manufacture and release throughout its period of storage and use (i.e., its shelf-life). All specification limits thus apply during stability studies and during the whole shelf life of the drug product until the end of the labeled expiry date (APIs: re-test period / retest date). Every pharmaceutical product on the market shall be so constituted that, if stored as directed, it will meet all applicable pharmacopoeial requirements and manufacturer's specifications until its expiration date. But which parameters need to be tested for medical cannabis during stability studies? And which requirements apply? Useful information in relation to these questions is provided in the following sections.

Stability Programme according to EU-GMP - What is required?

The stability programme designed in accordance with the ICH Q1 Guidelines on Stability is required to establish the shelf life of a product and for receiving a marketing authorization.

According to EU-GMP (Chapter 6), the manufacturer must have an ongoing stability programme to support the shelf life of the product. The programme shall meet ICH Q1 requirements. Bracketing and matrixing is possible according to ICH Q1 Guidelines ("Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied"). For multidose containers, in-use stability studies are required in principle according to EMA´s NOTE FOR GUIDANCE ON IN-USE STABILITY TESTING OF HUMAN MEDICINAL PRODUCTS. However, for example, stability testing is usually not required under GPP (e.g. Canada / NZ).

The specific requirements for stability testing of herbal drugs like Cannabis, which is a narcotic substance, are sometimes challenging. E.g. storage needs to be done in climate chambers in specifically designed and secured facilities. In addition, specific rules have to be followed concerning import/export (e.g. need for special licenses), transport (e.g. GDP + additional security measures), sample & waste handling and documentation.

How do CBD and THC degrade?

In an acidic milieu Cannabidiol (CBD) converts to Δ8- und Δ9-THC, whereas in an (highly) alkaline milieu, oxidation to a chinone due to reaction with oxygen occurs. During storage in presence of air, THC can be dehydrated to Cannabinol (CBN). CBN is also an oxidation product of Tetrahydrocannabinol (THC). Therefore, most of the national Pharmacopoeias set a limit of max. 1% for CBN (D, DK, CH) in flowers (D: in extracts max. 2.5%) and max. 1.5 % (Israela) as stability indicator. The USP Cannabis Expert Panelb proposes for THC-dominant and THC/CBD intermediate types that CBN is max. 2% of the content of total THC.

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More information is provided in the article "Thermal Stability of cannabinoids in dried cannabis: a kinetic study", from Juris Meija et al., published in Analytical and Bioanalytical Chemistry from January 2021. In addition, there is a free-of-charge simulator, based on the work of the same group - where it is possible to "play" with different initial cannabinoid values and temperatures and calculate the expected values after a certain time: Cannabis stability calculator (https://metrology.shinyapps.io/cannabis-calculator/).

Which Guidelines / Pharmacopoeias provide useful information?

General Applicable Guidelines from FDA and USP General Chapters

- ⟨1191⟩ Stability Considerations in Dispensing Practice: The chapter covers aspects of drug product stability that are of primary concern to the pharmacist in the dispensing of medications.
- ⟨1079⟩ Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products
- ⟨1149⟩ Guidelines for Assessing and Controlling the Physical Stability of Chemical and Biological Pharmaceutical Raw Materials, Intermediates, and Dosage Forms (the original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability).
- ⟨1207.1⟩ Package Integrity Testing in the Product Life Cycle-Test Method Selection and Validation
-  FDA Draft Guideline on Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research

Specific EU Guidelines for Stability / Herbal Drugs

For herbal drugs, herbal drug preparations and herbal medicinal products, (HMPs) reference is made to the stability section of the EMA Guideline on quality of herbal medicinal products (EMA/HMPC/201116/2005).

Further guidance is provided in:

- Start of shelf-life of the finished dosage form (Annex to guidance on the manufacture of the finished dosage form) - CPMP/QWP/072/96.
- Questions and answers on quality of herbal medicinal products - EMA/HMPC/41500/2010.
- Reflection paper on stability testing of herbal medicinal products - EMA/HMPC/3626/2009
- Guideline on stability testing for applications for variations to a marketing authorization - EMA/CHMP/CVMP/QWP/441071/2011.
- Guideline on stability testing: stability testing of existing active substances and related finished products - CPMP/QWP/122/02.
- Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products - EMA/HMPC/162241/2005.
- Guideline on quality documentation for medicinal products when used with a medical device - EMA/CHMP/QWP/BWP/259165/2019

Which parameters need to be tested during stability?

The question often is: Which parameters should be tested during stability? And: Do all parameters for release testing need to be tested during stability?
It is highly recommended to test the CBN content (degradation product) during stability studies (see above).
In addition, Malta´s General Guidelines on the production of Cannabis for medicinal and research purposes (Appendix I, Quality & Stability) proposes that stability tests must include, as a minimum, assays for THC & CBD, loss on drying (LOD), and microbiological contamination (see table 1).

Where applicable, the tests and limits provided in the European Pharmacopoeia (Ph. Eur.) general chapters Herbal Drugs, Herbal Drug Preparations and Herbal Drug Extracts must be followed (USP <561> Articles of Botanical Origin / <565> Botanical Extracts). In addition, the provisions of the national monographs (e.g. Dc, DKd, CHe, NZf) need to be applied, as well. Regarding the use of analytical methods, see also Ph. Eur. chapter 5.26. Implementation of pharmacopoeial procedures (new) and 5.27. Comparability of alternative analytical procedures (draft).

In case of extraction solvents being used, Residual Solvents (Ph. Eur. 5.4, USP <467>) and Identification and Control of Residual Solvents (Ph. Eur. 2.4.24) have to be considered (CoA). For raw materials coming from an outside source, further tests (e.g. fumigant residues, radioactivity) may be required.

Table 1: Proposed parameters for release and stability testing for Cannabis flowers

CERTIFICATE OF ANALYSIS (CoA)

STABILITY TESTING

CBN

CBN

Content THC*

Content THC*

Content CBD*

Content CBD*

LOD**

LOD**

Microbiological Contamination***

Microbiological Contamination***

Pesticides1

 

Heavy Metals1

 

Mycotoxins1

 

Foreign Matter

 

(Total Ash)****

 

Identity

*Assay limits
Cannabis flowers: Usually, the total THC / CBD content must be 90 - 110 % of the labelled content. However, this might be different, e.g., if the flowers are considered to be an API. The USP Cannabis Expert Panel, for example, recommends 80 - 120 %. 
DAB Cannabis Extract: THC content: 1 - 25 %. Total THC / CBD: 90 to 110 % of the labeled content.
Finished dosage form (e.g. Cannabis oil): Usually, the total THC / CBD content must be 95 - 105 % of the labelled content.

**Usually max. 10-15 %. The USP Cannabis Expert Panel proposes to perform water activity testing.

*** Ph. Eur. 5.1.8. / 5.1.4. [USP <1111>] (depending on the dosage form / route of application), see also: Reflection paper on microbiological aspects of herbal medicinal products (EMA/HMPC/95714/2013). Starting material / herbal drugs used for the production of extracts: Usually criteria of Ph. Eur. 5.1.8, category A might be acceptable. In the case that it is demonstrated that these limits cannot be met, higher limits must be sufficiently justified.

**** e.g., required in DK, NZ (usually max. 20 %)

1 Skip testing might be possible, if justified and authorized, based on data and risk assessment.


Terpenes: Where the amount of terpenes (or any other ingredient, including other cannabinoids) is specified and labelled, if intended as an active ingredient, then the content needs also to be tested via an (validated) assay during stability studies.

Where can I find information on reference substances?

In 2008, EMA´s HMPC published a Reflection Paper on Markers used for Quantitative and Qualitative Analysis of HMPs (EMEA/HMPC/253629/2007).
The HMPC recently announced to review Ph. Eur. definitions and HMPC monographs / assessment reports taking into account regulatory practice and different views on the role of active and analytical markers. A discussion paper will be drafted with proposals for better definitions considering existing Ph. Eur. defined extract types (particularly quantified extracts) [HMPC Work Plan 2022]. Further guidance (e.g. on characterization requirements for reference substances to be established as a primary standard) is provided in Ph. Eur. 5.12. Reference Standards.

The German Pharmacopoeia (Deutsches Arzneibuch, DAB) currently contains the two monographs Cannabis Flower and Cannabis Extract. Reference substances, such as cannabinol (CBN) and cannabidiol (CBD), are required for assay and purity tests, as well as for identity tests (TLC), specified therein. A notice from the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) dated from 9 February 2022 recommended the following revised reagent descriptions for inclusion in the DAB:

Cannabinol RN

Cannabidiol RN

Cannabidiolsäure RN (Cannabidiolic acid)

Delta-8-Tetrahydrocannabinol RN

Delta-9-Tetrahydrocannabinol RN

Delta-9-Tetrahydrocannabinol-Säure RN (Delta-9-Tetrahydrocannabinolic acid)

The revision concerns the change that 13C-NMR data can be used alternatively (or in addition to 1H-NMR data) for identification. Previously, substances must comply with 1H-NMR and 13C-NMR tests.

Ph. Eur. and USP

In the European Pharmacopoeia (Ph. Eur.), there are currently no Ph. Eur. reference substances for cannabis analysis provided (the Ph. Eur. Cannabis monographs for flowers and extracts are currently under development). However, the USP includes monographs for Dronabinol and CBD (draftg) and already offers several reference substances (see also USP's "Cannabis for medical use" website):

Delta-9-Tetrahydrocannabinol  

Exo-Tetrahydrocannabinol 

Cannabinoid Acids Mixture 

Cannabinoids Mixture 

Cannabidiol Solution  

Cannabidiol

Delta-8-tetrahydrocannabinol (Δ-8-THC) is described in the USP under "Reagents" ("Use a suitable grade, which may be a solid material or a solution in methanol"). Several supply sources for "suitable grade" Δ-8-THC are also listed there.

Post-Conference: Qualification & Validation Aspects for Cannabis - Live Online Conference

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Post-Conference: Qualification & Validation Aspects for Cannabis - Live Online Conference

References:

a) Israel Medical Cannabis (IMC) - GMP (SOP 152): Good Manufacturing Practice for Medical Cannabis Products.

b) Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes (J. Nat. Prod. 2020, 83, 1334-1351).

c) German Pharmacopoeia (DAB) Monographs Cannabis Flower and Cannabis Extract, Standardized

d) Danish Monograph Cannabis Flower (Dansk monografi Cannabisblomst)

e) Swiss Pharmacopoeia (Ph. Helv.) Monograph Cannabis Flower

f) New Zealand Product Quality Standards Monograph (Appendix 2 of the Medicinal Cannabis Scheme)

g) USP draft monograph Cannabidiol [Pharmacopeial Forum (PF) 48(1)]

 

Author:
Dr Andrea Kühn-Hebecker
... is Operations Director and organizes and conducts courses and conferences on behalf of the ECA Academy in the area packaging, herbal medicinal products, development and lifecycle management.

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