Guideline on Manufacture of the Finished Dosage …

1 30 Churchill Place Canary Wharf London E14 5EU United Kingdom An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.. 4 July 2017 EMA/CHMP/QWP/245074/2015 Committe e for H uman Medicinal P roducts (CHMP) Guideline on man ufacture of the Finished Dosage form Draft agreed by QWP, BWP February 2015 Adopted by CHMP for release for consulta tion 23 Apri l 2015 Start of publi c consulta tion 09 July 2015 End of consulta tion (deadline for comments)

2 09 January 2016 Agreed by QWP May 2017 Agreed by BWP June 2017 Endorsed by HMPC 18 July 2017 Adopted by CHMP 20 July 2017 Da te for comi ng into effe ct 6 months after publications This Guideline replaces the Note for Guidance on Manufacture of the Finished Dosage form (CPMP/QWP/486/95) Keywords Manufactur e, Finished product , process description, level of detail, technical adaptation, intermediate, bulk, storage, transport, CTD Guideline on Manufacture of the Finished Dosage form EMA/362427/2017 Page 2/15 Table of contents Executive 3 1. Introduction (backgr ound) .. 3 2. Sc ope .. 3 3. Legal basis.

3 3 4. Manuf acture .. 4 Manufacturer(s) .. 4 Batch 4 Description of Manufacturing Process and Process Controls .. 5 Controls of Critical Steps and Intermediates .. 7 Process Validation and/or Evaluation .. 9 Definitions .. 10 Control Strategy:.. 10 Critical Process Parameter (CPP): .. 10 Critical Quality Attribute (CQA): .. 10 Design Space: .. 10 Hold Time: .. 10 Real Time Release Test ing: .. 10 References .. 11 Annex .. 12 Guideline on Manufacture of the Finished Dosage form EMA/362427/2017 Page 3/15 Exec utive summary This Guideline replaces the note for guidance on the Manufacture of the Finished Dosage form (CPMP/QWP/486/95).

4 The note for guidance has been updated to reflect the requirements as laid down in the current legislation Directive 2001/83/EC, and to follow the format and content of the Common Technical Document (CTD) Module 3 dossier. It also addresses current manufacturi ng practices in terms of complex supply chains and world wide Manufacture . In addition, the content and pri nciples of the ICH Q8 Guideline (ref 1) are also taken into account. This Guideline does not introduce new require ments on authori sed medicinal products for human use. However as stated in artic le 23 of Dire ctive 2001/83/EC, after a marketing authori sation (MA) has been approved, the authorisation holder should, in re spect of the methods of Manufacture and contro l take account of scientif ic and technical pro gre ss and introduce any changes that may be require d to enable the medicinal product to be Manufacture d and controlled by means of generally accepted sci entif ic methods.

5 1. Introductio n (background) The objective of the Guideline on the Manufacture of the Finished Dosage form is to provide clarification on the type and level of information that should be included in the CTD Module 3 of the marketing authorisation application (MAA) dossier with respect to the manufacturing process description. This description should include information about critical steps and intermediates and provides a link between the pharmaceutical development, the proposed control strategy and process validation. The Guideline also addresses aspects related to outsourcing and new manufacturing practices such as complex manufacturing chains or issues with prolonged holding times and transportation conditions.

6 Detailed information about requirements of the sterilisation process is provided in a separate Guideline . 2. Scope This Guideline is applicable to the Manufacture of the Finished Dosage form of chemi cal and herb al medicinal products for human use intended for marketi ng authori sation. It also applies to variations for authori sed products in cases where changes to the manufacturi ng pro cess affectin g the MA are proposed. The principles described are in general also applicable to biological medicinal products. Where relevant, the principles of this Guideline may also be applied to radiopharmaceuticals and to chemical investig ational medicinal products.

7 3. Legal basis This Guideline should be re ad in conjunction with Dire ctiv e 2001/83/EC Article (d), as amended where it is stated that the applic ation for a marketi ng authori sation shall contain a description of the manufacturi ng method. The require ments on the description of the manufacturi ng method in the CTD Module 3 of marketi ng authori sation dossier are described in Annex 1, Part 1 (section ) to this Dire ctive. Further details on the information to be provided are outlined in this Guideline . Guideline on Manufacture of the Finished Dosage form EMA/362427/2017 Page 4/15 4. Manuf acture The headings of this Guideline follow the stru cture of the CTD format Module 3, Section Manufacture .

8 Only product specific aspects of Manufacture need to be described and included in the MA dossier; general elements of Good Manufacturi ng Practice (GMP), (ref. 3) should not be included. Manufacturer(s) For each stage of the manufacturi ng process, including packaging, details should be given of all the individual sites involved (including those from the same company). The name, address and responsibility of each manufacturer, including contractors, should be provided. This applies also to all quality control sites, including on-going stability testing if different from the manufacturing site(s). The EU site responsible for batch release in the EU market should be specified.

9 Batch Formula The batch formula for the intended batch size should be stated. In case a ra nge of batch sizes is proposed, the range should be stated and the batch formula should be pro vided for at least the largest and smallest batch sizes. An application for a range of batch sizes should be adequately justif ied as not adversely impacting the critical quality attributes (CQAs) of the Finished product in accordance with the Guideline on pro cess validatio n (ref. 4). If the bulk product is assembled into diffe re nt pre sentations or packs, the production batch size should be defined by the bulk before any division.

10 When the length of the subsequent pro cesses and assembly is considered critical ( filling time for aseptically Manufacture d products), the worst-case scenario of the division pattern ( in respect of total filling time) should be indicated. The batch size for a product to be marketed should normally be compatible with production scale equipment. It should be suffi ciently large to be representative of commercial manufacturing to enable demonstration of a state of control. For example, a commercial batch size for soli d oral Dosage forms should be at least 100,000 units unless justif ication is pro vided ( orp han medicinal products) (ref.)