TGA Consultation: Adoption of International Scientific Guidelines in Australia

The TGA is seeking feedback on whether or not certain international scientific guidelines should be adopted by Australia. The consultation, closing Monday 4 March 2024, considers the adoption of  13 international scientific guidelines, some of which have, or may have, relevance to the manufacture and/or supply of Listed, Assessed Listed, or Registered complementary medicines. Members are encouraged to review relevant guidelines to determine suitability to Australian complementary medicines application pathways. Direct feedback to TGA can be provided by the closing date by completing the online survey available on the TGA Consultation Hub. If areas of concern are identified please provide feedback to CMA, preferred by 28 February, via technical@cmaustralia.org.au.   

This tech alert provides a summary of the proposed guidelines that CMA consider are either: 

  1. Relevant to all complementary medicines including Listed medicines

Note: This part only contains reference to those international scientific guidelines that are adopted by way of the Therapeutic Goods Order 101 (elemental impurities and residual solvents). This is because CMA has previously received advice from the TGA that the use of European Union (EU) and ICH guidelines adopted in Australia and other Australia-specific guidelines is not specifically mandated in the legislation in relation to listed medicines. Whilst TGA guidance material (eg. Australian Regulatory Guidelines for Listed Medicines and Registered Complementary Medicines / ARGLMRCM) suggests sponsors should refer to certain guidelines to assist them to meet their legislative requirements, with regard to quality and safety for example, CMA is not aware of instances of these guidelines being applied to Listed medicines (other than for some new substance applications). The requirements specified in an adopted international guideline cannot be enforced for listed medicines unless failure to meet requirements in the guidelines also results in a specific breach of Australian Therapeutic Goods legislation. 

Also note that the Permissible Ingredients Determination is not currently used to specify requirements for Listed medicines to comply with international scientific guidelines. While it is possible that specific requirements that are outlined in scientific guidelines may be included for some ingredients in this Determination at a future date if the requirements are considered necessary to maintain the quality and/or safety of an ingredient, this would be subject to either consultation or discussion with an applicant during an application process. 

  1. May have relevance to Listed Assessed and Registered complementary medicines applications, or applications for new (or changed) substances to use in Listed medicines

Note: CMA has included guidelines we believe are relevant however we have sought confirmation from the TGA of the applicability of the guidelines under consultation to these CM application pathways and are waiting on further advice. 

E.g. For registered medicines (including complementary), under paragraph 25(1) the Act the delegate is required, when evaluating an application for registration, to consider: ‘…whether the quality, safety, and efficacy of the goods for the purposes for which [the goods] are to be used have been satisfactorily established.’  

Australia-specific guidelines and adopted EU and ICH guidelines describe the kind of data and information to be included in each Module of a dossier to demonstrate quality, safety, and efficacy. If the dossier does not contain all of this information, the TGA may not be able to determine whether the quality, safety and efficacy of the medicine has been satisfactorily established. See https://www.tga.gov.au/book-page/mandatory-requirements-1 for more information (scroll down to subsection Australia-specific and adopted European Union and ICH guidelines). 

  1. Proposed guidelines that are relevant to Listed, Assessed Listed and Registered CM 
  • ICH guideline Q3C (R8) on impurities: guideline for residual solvents Step 5 

This guideline is intended to replace the ICH guideline Q3C (R6) on impurities: guideline for residual solvents, already adopted by the TGA. This guideline will apply to Listed medicines as per section 16 of the TGO 101, the requirements for residual solvents are identified as being those provided in Ph. Eur 5.4, which incorporates the ICH Q3C guideline. 

This guideline recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. It recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. The document is intended to be read together with the annexes on Annexes to CPMP/ICH/283/95 impurities: Guideline for residual solvents & CVMP/VICH/502/99 guideline on impurities: Residual solvents – Revision 1

A comparison of the current Q3C (R6) and the proposed Q3C (R8) documents is available online here. The changes predominantly relate to: 

  • The removal of methyltetrahydrofuran from Table 4. –  Solvents for which no adequate toxicological data was found.  
  • The addition of Part VI: PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether, and Tertiary-Butyl Alcohol (pp 41-51).   
  • Cyclopentyl Methyl Ether: 15.0 PDE (mg/day); 1500PPM. 
  • Tertiary-Butyl Alcohol: 35 PDE (mg/day); 3500PPM. 
  • 2-Methyltetrahydrofuran 50 PDE (mg/day). 
  • ICH guideline Q3D (R2) on elemental impurities Step 5 

The ICH Q3D is adopted for medicines including Listed medicines by section 16 of the TGO 101. Per the TGO 101 guidance, for lead, arsenic, cadmium and mercury, compliance to either USP<2232> or ICH Q3D is acceptable. Both documents provide guidance on methods for establishing maximum values for elemental impurities based on the permitted daily exposure (PDE) of each element. 

The Q3D document presents a process to assess and control elemental impurities in finished product using the principles of risk management as described in ICH Q9 (quality risk management). This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the finished product 

The EMA website provides that new/revised guideline sections are to be included in the Q3D on elemental impurities – Step 5 – Revision 2 guideline effective from 24 September 2022. Training modules for the implementation of Revision 2 of the guideline can be found on the ICH’s website

A comparison of the current Q3D (R1) and the proposed Q3D (R2) documents is available online here. The changes predominantly relate to: 

  • Correction of PDEs for Gold (Oral), Silver (parenteral) and Nickel (inhalation) – Appendix 2 (pp. 28-9). 
  • Correction of Gold and Silver monographs: 
  • Gold –  correction to PDE (p. 47) 
  • Silver – correction to PDE – Parenteral exposure (pp. 73-4). 
  • Addition of appendix 5: limits for elemental Impurities by the Cutaneous and Transcutaneous Route (pp. 91-100). 
  • Editorial corrections, including addition of brackets around denominator in PDE formulas. 
  1. Proposed guidelines that may have relevance to applications for Listed Assessed or Registered complementary medicines, or applications for new (or changed) substances in Listed Medicines. 

Note: CMA are awaiting further TGA advice and clarity on the applicability of a number of the guidelines to complementary medicine pre-market applications. Until confirmation is received, CMA believe the following guidelines are likely to be considered, where relevant and applicable, to individual pre-market applications for new (or changed) substances in listed medicines, Assessed Listed or Registered CM. 

  • ICH guideline E8 (R1) on general considerations for clinical studies Step 5 

This guideline provides guidance on the clinical development lifecycle, including designing quality into clinical studies, considering the broad range of clinical study designs and data sources used. The document is intended to:   

  1. Describe internationally accepted principles and practices in the design and conduct of clinical studies that will ensure the protection of study participants and facilitate acceptance of data and results by regulatory authorities. 
  1. Provide guidance on the consideration of quality in the design and conduct of clinical studies across the product lifecycle, including the identification, during study planning, of factors that are critical to the quality of the study, and the management of risks to those factors during study conduct. 
  1. Provide an overview of the types of clinical studies performed during the product lifecycle, and describe study design elements that support the identification of quality factors critical to ensuring the protection of study participants, the integrity of the data, the reliability of results, and the ability of the studies to meet their objectives. 
  1. Provide a guide to the ICH efficacy documents to facilitate user’s access. 
  • ICH guideline M10 on bioanalytical method validation and study sample analysis Step 5 

This guideline is intended to provide recommendations for the validation of bioanalytical methods for chemical and biological drug quantification and their application in the analysis of study samples. The document describes the validation of bioanalytical methods and study sample analysis that are expected to support regulatory decisions and  is applicable to the bioanalytical methods used to measure concentrations of chemical and biological drug(s) and their metabolite(s) in:  

  • biological samples (e.g., blood, plasma, serum, other body fluids or tissues) obtained in nonclinical toxicokinetic (TK) studies conducted according to the principles of Good Laboratory Practice GLP; 
  • nonclinical pharmacokinetic (PK) studies conducted as surrogates for clinical studies; and 
  • all phases of clinical trials, including comparative bioavailability/bioequivalence (BA/BE) studies. 

The information in this guideline applies to the quantitative analysis by ligand binding assays (LBAs) and chromatographic methods such as liquid chromatography (LC) or gas chromatography (GC), which are typically used in combination with mass spectrometry (MS) detection. For studies that are subject GLP or Good Clinical Practice (GCP) the bioanalysis of study samples should also conform to their requirements. 

  • ICH Electronic Common Technical Document (eCTD) v4.0 Implementation Guide v1.5 

This document provides instructions on how to implement the Electronic Common Technical Document (eCTD) v4.0 specification. This document only includes the specification information for eCTD v4.0 Modules 2 – 5 submission contents. eCTD v4.0 aims to facilitate the processing and review of electronic regulatory submissions by: 

  • Document Reuse – the ability to submit a document once to a Regulatory Authority and refer to the document by its unique identifier in future submissions if the document is validly retained by the Regulatory Authority. 
  • Document and Metadata life cycle – the ability to manage the versions of documents and/or metadata. 
  • Management of Context Groups – the ability to group documents together based on nature of their use (e.g., components of clinical study reports). 
  • ICH M9 guideline on biopharmaceutics classification system-based biowaivers Step 5 

The ICH M9 guideline on biopharmaceutics classification system-based biowaivers has an associated EMA questions and answers document addressing Biopharmaceutics classification of the drug substance (Solubility & Permeability), and  Eligibility of a drug product for a BCS based biowaiver (Excipients  & In vitro Dissolution). The document also contains an Annex linking Q&As to the respective sections of ICH M9 Guideline.  

A summary of the scope of the guideline is provided below. 

  • The BCS (Biopharmaceutics Classification System)-based biowaiver approach is intended to reduce the need for in vivo bioequivalence studies i.e., it can provide a surrogate for in vivo bioequivalence. In vivo bioequivalence studies may be exempted if an assumption of equivalence in in vivo performance can be justified by satisfactory in vitro data. The BCS is a scientific approach based on the aqueous solubility and intestinal permeability characteristics of the drug substance(s). 
  • This guidance provides recommendations to support the biopharmaceutics classification of drug substances and the BCS-based biowaiver of bioequivalence studies for drug products.  
  • The BCS-based biowaiver is only applicable to immediate release, solid orally administered dosage forms or suspensions designed to deliver a drug to the systemic circulation. Drug products having a narrow therapeutic index are excluded from consideration for a BCS-based biowaiver in this guidance. Fixed-dose combination (FDC) products are eligible for a BCS-based biowaiver when all drug substances contained in the combination drug product meet certain criteria (as defined in sections 2 and 3 of the guidance). 
  • Nonclinical safety testing in support of development of paediatric pharmaceuticals S11 
  • This Guideline provides direction on the nonclinical safety studies important to support a paediatric development programme. It recommends standards for the conditions under which nonclinical juvenile animal testing is considered informative and necessary to support paediatric clinical trials, and also provides guidance on the design of the studies. A streamlined drug development and higher scientific rigor while minimizing the unnecessary use of animals will be achieved with the implementation of this new Harmonised ICH Guideline. https://ich.org/news/ich-s11-reaches-step-4-ich-process  
  • The purpose of this document is to recommend international standards for, and promote harmonisation of, the nonclinical safety assessments to support the development of pharmaceuticals intended for paediatric use. 
  • This guideline is intended to complement and expand on existing ICH guidelines (e.g., ICH E11, M3, S5 and S9). 
  • This guideline recommends an approach for the nonclinical safety evaluation of pharmaceuticals intended for development in paediatric populations. This can include products with prior adult use, as well as products being considered for initial human use in paediatrics. 
  • ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population Step 5 – Addendum 

This document provides an outline of critical issues in paediatric drug development and approaches to the safe, efficient, and ethical study of medicinal products in the paediatric population. The purpose of this addendum is to complement and provide clarification and current regulatory perspective on topics in paediatric drug development. 

It is unclear whether the above two guidelines apply to CM as it refers to drug development, however it is possible it could be applied to applications for CM paediatric products. 

  • ICH guideline S1B(R1) on testing for carcinogenicity of pharmaceuticals Step 5 

This guideline replaces the ICH Topic S1B Carcinogenicity: Testing for Carcinogenicity of Pharmaceuticals guideline, already adopted by the TGA. The guideline embraces all pharmaceutical agents that need carcinogenicity testing as indicated in Guideline S1A (any pharmaceutical whose expected clinical use is continuous for at least 6 months). 

This guideline is most likely to apply to some new (or changed) substance applications. 

  • ICH M7(R2) Addendum on application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes Step 5 

The ICH M7 Guideline discusses the derivation of Acceptable Intakes (AIs) for mutagenic impurities with positive carcinogenicity data. In this Addendum to ICH M7, AIs or Permissible Daily Exposures (PDEs) have been derived for a set of chemicals that are considered to be mutagens and carcinogens and are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M7. 

CMA notes that mutagenic impurities are more associated with pharmaceutical substances than complementary medicines. Recently calcium folinate was established as having non-mutagenic nitrosamine impurities. 

  • ICH M7(R2) Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk Step 5 

CMA notes this guideline may apply to some new substance applications for listed medicines but is specified as not applying to herbal products or crude products of animal or plant origin. 

This guideline replaces the ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, already adopted by the TGA. It is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing. 

It also applies to post-approval submissions of marketed products, and to new marketing applications for products with a drug substance that is present in a previously approved product, in both cases only where: 

  • Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities;  
  • Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products;  
  • Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level. 

Assessment of the mutagenic potential of impurities as described in the guideline is not intended for the following types of drug substances and drug products: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation products, herbal products, and crude products of animal or plant origin. 

Other guidelines under consultation 

CMA does not believe the following guidelines will be relevant to any usual complementary medicines (unless they are evaluated as prescription medicines). 

  • Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies 
  • Guideline on the evaluation of anticancer medicinal products in man 

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