Congratulations to our colleague Leslie Dowling who recently received a Distinguished Service Award from TOPRA. Being a well-practiced multitasker, Leslie also heads up our UK office as Managing Consultant. Having worked in regulatory affairs since 1997, mainly in human medicines, but also encompassing medical devices and veterinary medicines, Leslie is experienced in managing multiple regulatory projects simultaneously, working in matrix organisations, both within small/medium pharma and as consultant/CRO with small/medium/large pharma clients.
(Photograph courtesy of TOPRA symposium 2017, Bob Clay, TOPRA President presents Leslie Dowling with TOPRA Distinguished Service Award)
This draft guideline was issued for consultation by EMA between 9 July 2015 and 9 January 2016. To date, it remains in draft. However, in our experience many of the requirements of this guideline are already being requested during product assessments by EU competent authorities.
Therefore, this article serves as a reminder that, according to EMA “This guideline replaces the note for guidance on the manufacture of the finished dosage form (CPMP/QWP/486/95). The note for guidance has been updated to reflect changes to the format and content of the Common Technical Document (CTD) Module 3 dossier. It also addresses current manufacturing practices in terms of complex supply chains and worldwide manufacture. In addition, the content and principles of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q8 guideline (ref. 1) is also taken into account.”
We have compared the text of the draft guideline with that of the very outdated 1996 guideline, and have summarised the main differences here. It is immediately evident that this is a complete and welcome rewrite of the guideline, reflecting current assessment practices.
The draft guideline is applicable to chemical and herbal medicinal products, and in general also to biological medicinal products – which were specifically excluded from the old guideline – but not to advanced therapy medicinal products. The principles of the draft guideline may be applied to radiopharmaceuticals and investigational medicinal products where relevant.
Reference to GMP
In the old guideline, the exclusion of information falling within the field of GMP and not relevant to the application for marketing authorisation was explained in considerable detail. This has now been replaced by a simple statement that ‘general elements of GMP should not be included’.
The ‘Description of the manufacturing chain’ has been replaced by Section 4.1 Manufacturer(s). This is similar to the superseded text, but clarifies that the names, addresses and responsibilities of all the individual sites involved, including contractors, should be stated.
The section on the ‘Manufacturing Formula’, now Section 4.2 Batch Formula, has been extensively rewritten. The text regarding the qualitative and quantitative statement of ingredients, overages, and factorisation has remained essentially the same. However, the draft guideline clamps down on batch sizes, clarifying that batch formulae should be presented for at least the highest and lowest batch sizes in case of a range of batch sizes. The formulae and numbers of sub-batches should be stated and justified. The old guideline was quite lenient with regard to actual quantities of ingredients compared to nominal quantities, whereas the draft guideline proposes that upper and lower acceptance limits may be proposed only when justified.
Manufacturing process and process controls, critical steps and intermediates
In the draft guideline, Sections 4.3 and 4.4 covering the description of manufacturing process and process controls as well as controls of critical steps and intermediates, taken together with a new annex, are almost seven times the length of the superseded text in the old guideline. The draft text covers:
- General aspects. Any special environmental conditions required during manufacture should be stated, as well as equipment type and size. More information must now be provided about the frequency of in-process controls and the in-process sampling strategy. Process parameters with target values or ranges must be provided; wide ranges or upper/lower limits alone require strong justification.
- Expected level of detail in the manufacturing process description (supplemented by the annex, see below). General references to ‘suitable’ equipment and ‘typically’ set points are no longer acceptable. This great favourite of many a CMC department has been deleted: It is in the interest of both the applicant and the regulatory authorities to avoid unnecessary applications for variations. Very detailed descriptions of the manufacturing process, apparatus and in-process controls should therefore be avoided.
- Technical adaptations in the manufacturing process for manufacture at different sites. Manufacturing processes using completely different principles are not acceptable, e.g. terminal sterilisation versus aseptic manufacture, or wet granulation versus dry granulation.
- Section 4.4 on Controls of Critical Steps and Intermediates now incorporates guidance on bulk storage, based on the EMA Q&A on Quality Part 2, published in 2012, which introduced guidance on stability issues of pharmaceutical bulk products used in manufacture of the finished product through seven questions on the subject.
Annex on expected level of detail
The new and very useful annex explains the expected level of detail in the description of the manufacturing process by using a 200 mg tablet manufactured by high shear wet granulation as an example, also clarifying differences between traditional and QbD applications.
The ‘Special Items’ section of the old guideline has been eliminated completely. This section covered Method of Sterilisation (the draft guideline simply cross-refers to a separate guideline for guidance on sterilisation), Re-processing of residual product, Removal of solvents or gases, Cleaning of primary packaging material, Sterilisation of primary packaging material, and Production areas.
The section on process validation has also been eliminated and replaced by a cross-reference to the relevant guideline in Section 4.5.
The draft guideline introduces a glossary (Definitions).
For assistance in interpreting the draft guideline and preparing for its implementation, please do not hesitate to get in touch with us using the contact form.
We are thrilled to announce several promotions within Real Regulatory.
Dorothée Fouchier has been promoted to Managing Consultant of our Dublin office. Dorothée joined the company in 2006 and during her time with us she has managed Real Regulatory’s in-company and consulting services to provide clients with the strategic advice and guidance they need for a flawless approach to meeting regulatory requirements.
Lucy Herlihy is now our Regulatory Affairs Manager. Lucy has been with Real Regulatory since 2010 and now has over 12 years regulatory affairs experience specialising in pharmaceutical regulatory affairs. Her main focus is in the CMC arena, project management and pharmaceutical regulatory affairs.
Fiona Windsor has advanced to become our Office Manager, a position that is greatly suited to her talents and experience. With over 15 years’ experience in administration throughout various industries, Fiona’s role is integral to the smooth day to day running of the office.
Further details on the RRL team can be found here.
Do you have an innovative product? Are you a Small or Medium Enterprise needing assistance to fully capitalise your product’s potential?
The pressure on companies to raise capital and fully maximise the potential of new drug candidates is ever growing. The cost of development is ever rising and the battleground for finance is becoming increasingly competitive. With pressure from all nations to reduce healthcare budgets, it has never been more important for companies to keep costs to a minimum and maximise value of their new products.
Regulatory Agency Initiatives
Regulatory agencies are increasingly looking to support the development of innovative medicines and have established schemes to do so. The agencies are promoting that companies seek to liaise with them as early as possible in the development programme ensuring that neither time or money are wasted during the development of potential new drugs.
Whether you are still at the bench progressing towards your first clinical trial or have already begun your clinical development programme Real Regulatory can support you in maximising the potential of your product enabling you to progress its development to your full capabilities.
We can assist you with the development and writing of documentation essential to the compilation of a Clinical Trial Application and progression towards agency approval to conduct a clinical trial, including the Investigational Medicinal Product Dossier (non-clinical, clinical, CMC and benefit/risk sections), Investigator Brochure and study Protocol.
We can advise and assist you with regulatory agency interactions enabling you to avail of the regulatory agency initiatives which have been established to support drug development.
We can support you across a range of agency interactions including:
- SME classification with the EMA allowing any company granted such status to avail of incentives offered to SMEs by the EMA
- scientific advice meetings to discuss your proposed development programmes across all aspects
- early interaction with national agencies and the EMA to participate in schemes to facilitate early access to new medicines, such as the Early Access to Medicines Scheme conducted by the MHRA or the Priority Medicines (PRIME) scheme conducted by the EMA
- orphan medicinal product designation applications. Increasingly additional sources of funding and grants are being made available by organisations to products with orphan designation.
Real Regulatory are ideally positioned to provide specialist expertise supplemented with the support from our panel of product development experts, to aid you in maximising the potential of your product.
To discuss your needs further please contact us.
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Real Regulatory Ltd is a team of proven and committed experts specialising in European Regulatory Affairs, Quality Management Systems and Supply Chain Operations Compliance.
We have a strong track record of delivering excellent results to our clients. Our focus is on completing projects on time, customising the solutions to your specific requirements, adapting to your existing processes, and generally contributing to your success through our in-depth knowledge of the relevant regulatory affairs issues.