Draft guideline on manufacture of the finished dosage form


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.

The draft guideline was issued for consultation on 9 July 2015. Consultation ends on 9 January 2016.

We at Real Generics have compared the text of the draft guideline with that of the heavily outdated 1996 guideline, and have summarised the main differences here.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 This has now been replaced by a simple statement that ‘general elements of GMP should not be included’.


The ‘Description of the manufacturing chain’ has been replaced by Section 4.1 Manufacturer(s). This is similar to the superseded text, but clarifies that the names, addresses and responsibilities of all the individual sites involved, including contractors, should be stated.

Batch formula

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.

Eliminated text

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).


Real Generics Ltd is a member of the Real Regulatory Group. The partner company, Real Regulatory Ltd, is a consultancy firm specialising in European Regulatory Affairs, Quality Management Systems and Supply Chain Operations Compliance for the pharmaceutical, medical device and aligned industries.

For assistance in interpreting the draft guideline and preparing for its implementation, as well as other regulatory intelligence needs, please do not hesitate to get in touch with us using the contact form.


Photograph courtesy Steve Jurvetson

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