ICH Update: GMPs for APIs and Starting Materials on the Agenda

The International Conference on Harmonization (ICH) is an important mechanism for facilitating harmony in pharmaceutical regulation among the US, the European Union, and Japan. The ICH and its Expert Working Groups met in Fukuoka, Japan in June 2015 to discuss the progress of key ICH initiative, and the ICH will meet again in December in Jackonsville, Florida. So what were the key items discussed for pharmaceutical manufacturing? DCAT Value Chain Insights (VCI) takes an inside look.

Among key recent items discussed at ICH's June meeting were updates to good manufacturing practices for active pharmaceutical ingredients (APIs) as well as decisions to begin work on guidelines for technical and regulatory considerations for pharmaceutical product lifecycle management and to develop Q&As on selection and justification of starting materials for the manufacture of drug substances.

Reform to ICH
At the June meeting, the ICH Steering Committee (SC) agreed on the key issues relating to the reform of ICH in terms of the Articles of Association, funding model and membership. An important part of the reform effort is establishing a formal organization with a new approach to membership, governance, and shared funding among ICH members. During a special session on June 10, interested parties were updated on the future of ICH, including issues regarding membership and governance of the new association. All participants welcomed the goals of the reform and recognized the intended roles of the Assembly as well as the Management Committee, according to an ICH press statement. Most participants indicated their interest for becoming ICH members or observers and the different intended eligibility criteria were discussed. The new ICH Association under Swiss law is expected to be established over the coming months with the aim of being operational starting in 2016.

Progress at the June meeting
Twelve working groups met in Fukuoka and achieved progress towards their respective objectives. The Question & Answer (Q&A) document on the Q7 Guideline on Good Manufacturing Practices for Active Pharmaceutical Ingredients (APIs) was signed off at Step 4 in Fukuoka and is ready for implementation in the ICH regions. In addition, two documents, the draft Addendum to the M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk document and the draft Addendum to E6 on Good Clinical Practice have reached Step 2b and will be submitted to public consultation.

With regard to quality guidelines, the Q7 Implementation Working Group (IWG) on Good Manufacturing Practices for APIs reached agreement on the Step 3 Q&A document ahead of the Fukuoka meeting. The SC approved this document for release by signing off Step 4 in Fukuoka and now enters the implementation period (Step 5). Step 4 is reached when the ICH Steering Committee agrees that there is sufficient consensus on a draft guideline. The Step 4 Final Document is signed-off by the SC signatories for the regulatory parties of ICH as an ICH Harmonized Guideline at Step 4 of the ICH process. Step 5 is regulatory implementation. This step is carried out according to the same national/regional procedures that apply to other regional regulatory guidelines and requirements, in the European Union, Japan, the Unites States, Canada, Switzerland and beyond.

According to ICH, experience gained with the implementation of the ICH Q7 Guideline since its finalization in 2000 shows that uncertainties related to the interpretation of some sections exist. Technical issues with regard to GMP of APIs, also in context with new ICH Guidelines, are addressed in this Question and Answer document in order to harmonize expectations during inspections, to remove ambiguities and uncertainties, and also to harmonize the inspections of both small molecules and biotech APIs. The Pharmaceutical Inspection Co-operation Scheme (PIC/S) contributed to the ICH document by selecting and reviewing relevant Q&As that had been collected from training sessions since the implementation of ICH Q7 and transferred the output of these reviews to the ICH Q7 Implementation Working Group for consideration and consolidation. Additional questions were developed based on responses from an ICH survey. PIC/S further contributed to the development of the document as an ICH Interested Party.

The SC also signed-off on Step 2a/2b of the Q3C(R6) Guideline for Residual Solvents, including two solvents: triethylamine and methyl isobutyl ketone. The Q3C maintenance EWG had reached agreement on this document ahead of the Fukuoka meeting The Q12 EWG on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management met for the second time in Fukuoka. This group is expected to finalize its Step 1 technical document in June 2016. The ICH SC approved an interim face-to face meeting of the Q11 IWG to develop Q&As on Selection and Justification of Starting Materials for the Manufacture of Drug Substances in September 2015. Multidisciplinary Guidelines Update.

The M2 EWG on Electronic Standards for the Transfer of Regulatory Information (ESTRI) met in Fukuoka, making progress on a variety of issues. The M4E(R2) EWG working on the revision of the Common Technical Document (CTD) Efficacy Guideline to provide greater specificity on the format and structure of benefit-risk information also made progress to finalise a draft of its Step 1 technical document. The M8 EWG on electronic Common Technical Document (eCTD) met in Fukuoka and the SC signed-off at Step 4 of Version 1.27 of the eCTD Change Request Q&A document and endorsed that the M8 would update the Granularity Document based on Q&A from CTD-Quality and change requests M8 received. The M8 EWG reconciled all of the comments received on the draft eCTD Implementation Guide v.4.0 during Step 3.

With respect to safety guidelines, the M7 EWG reached agreement on the draft Addendum to the Guideline Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. The SC signed off the Step 2a/2b document in Fukuoka. thus releasing this document for public consultation. A new EWG, S5(R3), was created to revise the Guideline on Detection of Toxicity to Reproduction for Medical Products and Toxicity to Male Fertility and met in Fukuoka for the first time. This group made good progress in reviewing and revising the current guidance in developmental and reproductive toxicity studies and expects to reach Step 2 by June 2017. It was also the first meeting of the S11 EWG tasked to develop a new ICH Guideline on Nonclinical Safety Testing in Support of Development of Pediatric Medicines.

With respect to efficacy guidelines, the EWG developed an Addendum to E6 on Good Clinical Practice to promote innovative approaches to clinical trial design, management, oversight and conduct made good progress and reached Step 2a/2b. The draft document that will take the format of an integrated addendum will now be submitted to public consultation. The EWG developing an Addendum to E9 on Choosing the Appropriate Estimand and Defining Sensitivity Analyses in Clinical Trials, met to focus on harmonizing improved clinical trial planning, conduct, analysis, and interpretation. The E11 EWG worked to develop an Addendum to the Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population and made good progress towards the draft Step 1 technical document. Step 2 for this topic is expected in December 2015.

The E14 Discussion Group (DG) met to develop a Concept Paper to revise the ICH E14 Guideline on the Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. During the meeting in Fukuoka, the SC endorsed the Concept Paper on the revision of the Q&A 5.1 on Concentration-Response Modelling for regulatory decision making thereby allowing experts to initiate this revision. The group working on the development of the E17 Guideline on Multi-regional Clinical Trials progressed towards developing the Step 1 technical document.

The E18 EWG on Genomic Sampling Methodologies for Future Use made progress towards a Step 2 document which is expected in December 2015. This Guideline will clarify points to consider in collecting genomic samples in clinical trials, resulting in further implementation of genomic research for the benefit of all stakeholders.

The regulatory agencies in the ICH regions also moved forward with recently adopted ICH guidelines. The US Food and Drug Administration (FDA) issued final guidance, Q3D Elemental Impurities in line with the guideline on elemental impurities adapted by the ICH. The ICH guideline was endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2014, and revised to correct several inconsistencies, December 2014. At Step 4 of the process, the final draft was recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. The guidance centers on three main areas: (1) the evaluation of the toxicity data for potential elemental impurities; (2) the establishment of a permitted daily exposure (PDE) for each element of toxicological concern; and application of a risk-based approach to control elemental impurities in drug product. The guidance presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product. The elements included in this guidance have been placed into three classes based on their toxicity (PDE) and likelihood of occurrence in the drug product. The likelihood of occurrence is derived from several factors including: probability of use in pharmaceutical processes, probability of being a co-isolated impurity with other elemental impurities in materials used in pharmaceutical processes, and the observed natural abundance and environmental distribution of the element. The guidance applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or nonrecombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this guidance, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.

The next ICH meeting will be held in Jacksonville, Florida, USA on December 5 – 10, 2015.

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