MHRA Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017

This is the 2017 edition of Rules and Guidance for Pharmaceutical Manufacturers and Distributors (the “Orange Guide”). Now in its 10th edition the guide has been updated with revised sections on:

qualiﬁcation of suppliers and customers;
parallel importation and parallel distribution;
temperature control and monitoring;
UK legislation; and
matters relating to unlicensed medicines.

There are also new MHRA sections on:

GMP for Excipients;
Guidance on revised Annex 16 of GMP; and
MHRA Data Integrity deﬁnitions and guidance for Industry.

Revised Annexes 15 and 16 are included. Also included is new Commission guidance on:

principles and guidelines of Good Manufacturing Practice for active substances;
principles of Good Distribution Practice of active substances;
setting health-based exposure limits; and
formalised risk assessment for ascertaining the appropriate GMP for excipients.

The EU regulation on safety featuresfor medicines is added together with two Commission Q&As on:

importation of active substances; and
safety features for medicinal products.

There is also anew appendix on sources of useful information.

GMP Directive

The principles and guidelines of GMP are adopted by the European Commission under powers conferred by Council Directive 2001/83/EC. This is to ensure that all medicinal products for human use manufactured or imported into the Community,including medicinal products intended for export, are to be manufactured in accordance with the principles and guidelines of GMP. The objective of GMP is to ensure that products are consistently produced and controlled to particular quality standards. Commission Directive 2003/94/EC (the “GMP Directive”) sets out the requirement srelating to the implementation of GMP for medicinal products for human use (currently including investigational medicinal products (IMPs)).

Regulation (EU) No 536/2014, on clinical trials on medicinal products for human use, requires the Commission to adopt delegated acts to specify the principles and guidelines of good manufacturing practice and the detailed arrangements forinspectionfor ensuring the quality of investigational medicinal products. Consequently it is therefore necessary that Directive 2003/94/EC be repealed and replaced by a Delegated Act on principles and guidelines of good manufacturing practice for investigational medicinal products and anew Implementing Directive on principles and guidelines of good manufacturing practice for medicinal products.

There will be three areas of GMP legislation when these two new Delegated Acts on principles and guidelines of GMP are in place alongside Delegated Regulation 1252/2014 on GMP for active substances.

Apublic consultation took place from 28 August to 24 November 2015 on the Commission Implementing Act on principles and guidelines on good manufacturing practice for medicinal products for human use. The new Delegated Acts for investigational medicinal products and ﬁnished products are planned to come into effect at the same time as the clinical trials Regulation 536/2014.

Changes to the Community Code

The Falsiﬁed Medicines Directive 2011/62/EU amends Directive 2001/83/EC in a number of places. The ﬁrst tranche of these changes in relation to manufacturing, wholesale dealing, supervision and sanctions came into force from 2 January 2013 with others relating to the importation of active substances from countries outside the European Economic Area (EEA) taking effect from 2 July 2013. These provisions are implemented in the UK by Regulations amending the Human Medicines Regulations 2012. The headline changes are as follows:

The current regulatory expectation for the manufacturer of the medicinal product to have audited their suppliers of active substances for compliance with the relevant GMP has been for malised, as is the requirement for the written conﬁrmation of audit (the “QP Declaration”, currently required as part of the marketing authorisation application). This audit may be undertaken by the manufacturer of the medicinal product, or by asuitable and appropriately experienced third party under contract to the manufacturer of the medicinal product.
In additional formal requirement for manufacturers of medicinal products (or athird party acting under contract) to audit their suppliers of active substances for compliance with the requirements of Good Distribution Practice (GDP) particular to active substances has also been introduced.
Manufacturers, importers and distributors of active substances now have to be registered with the competent authority of the Member State in which they are established (in the UK this is MHRA). Registrations are entered onto a data base operated by the European Medicines Agency,in a similar manner to the Eudra GMDP database. The manufacturer of the medicinal product must verify that their suppliers of active substances are registered.
Manufacturers of the medicinal product have to verify the authenticity and quality of the active substances and excipients they use.
The manufacture of active substances for use in licensed medicinal product must be in compliance with the relevant GMP. These standards are currently described in Part II of the EU Guidelines on GMP.
Active substances imported from outside the EEA must have been manufactured in accordance with standards of GMP, atleast equivalent to those in the EU, and from 2 July 2013 must be accompanied by a written conﬁrmation that equivalent GMP standards and supervision apply in the exporting country,unless the active substance is sourced from acountry listed by the European Commission or,exceptionally and where necessary, toensure availability of medicinal products, an EU GMP certiﬁcate for the site of manufacture is available.
Manufacturers of medicinal products have to assess the risk to product quality presented by any excipients they use, by way of a formalised documented risk assessment, and ascertain the appropriate good manufacturing practices necessary to assure their safety and quality. There is no explicit obligation for the medicinal product manufacturer to audit their suppliers of excipients, but the manufacturer is required to assure themselves that the appropriate good manufacturing practices are being applied.
In support of the above changes the European Commission has adopted the following by means of delegated acts and guidelines:

– principles and guidelines for GMP for active substances;

– GDP guidelines for active substances; and

– guidelines for the formal risk assessment process for excipients.

Manufacturers, wholesale distributors and brokers of medicines have to inform the competent authority and the marketing authorisation holder (MAH) should information be obtained that products either manufactured under the scope of the manufacturing authorisation or received or offered may be falsiﬁed, whether those products are being distributed through the legitimate supply chain, or by illegal means.
Brokers of medicines have to be registered with the competent authority of the Member State in which they are established (in the UK this is MHRA) and must comply with the applicable aspects of GDP.
Persons undertaking the wholesale distribution of medicinal products to third countries have to hold an authorisation and have to check that their customers are authorised to receive medicines. Where the medicinal products for export have been imported fromathird country,checks must also be made to ensure the supplier is authorised to supply medicines.
n extension of the requirement to notify MHRA and the MAH where a wholesale dealer imports from another EEA Member State into the UK amedicinal product that is the subject of anational marketing authorisation, and the importer is not the MAH or acting on the MAH’s behalf, for centrally authorised products (those holding amarketing authorisation granted by the European Medicines Agency), and the introduction of the option for the competent authority to charge afee for processing the notiﬁcation. For products imported into the UK the competent authority would be either the European Medicines Agency or MHRA, depending on whether the product is centrally authorised or not.

Changes to the EU Guide to GMP

Following earlier restructuring of the GMP Guide publication to create PartII(Basic Requirements for ActiveSubstances used as Starting Materials), in December 2010, anew Part III to the EC GMP Guide was created containing acollection of GMP-related documents, which are not detailed guidelines on the principles of GMP laid down in Directives 2003/94/EC and 91/412/EC. The aim of Part III is to clarify regulatory expectations and it should be viewed as asource of information on current best practices. Details on the applicability will be described separately in each document. Part III previously contained ﬁve documents: Explanatory Notes on the Preparation of aSite Master File, ICH guideline Q9 on quality risk management, ICH guideline Q10 on pharmaceutical quality system, Internationally Harmonised Requirements for Batch Certiﬁcation and atemplate for the “written conﬁrmation” for active substancesexported to the EU. Part III has been revised and now includes guidelines on setting health-based exposure limits for use in risk identiﬁcation in the manufacture of different medicinal products in shared facilities and guidelines on theformalised risk assessmentfor ascertainingthe appropriate GMP for excipients.

New/revised annexes

Annex 15 has been revised to take into account changes to other sections of the EudraLex, Volume 4, Part I, relationship to Part II, Annex 11, ICH Q8, Q9, Q10 and Q11, QWP guidance on process validation, and changes in manufacturing technology.
Annex16has also been revised toreﬂectthe global isationofthe pharmaceutical supply chains andthe introduction of new quality control strategies.The revision hasbeencarried outinlight of Directive 2011/62/EU amending Directive 2001/83/ECasregards thepreventionofthe entry into thelegal supply chainoffalsiﬁedmedicinal products. This version also implements ICHQ8, Q9 andQ10 documents, andinterpretation documents, such as themanufacturing andimportation authorisation (MIA)interpretationdocument, as applicable.Also, some areaswhere the interpretation by Member States hasnot been consistent,havebeen clariﬁed.Thisrevised Annexcameintooperation 15 April2016.

New guidelines

Commission Delegated Regulation (EU) No 1252/2014 of 28 May 2014 supplementing Directive 2001/83/EC of the European Parliament and of theCouncil with regardtoprinciplesand guidelinesofgood manufacturing practice for active substances for medicinal products for human use. This Regulation lays down the principles and guidelines of good manufacturing practice foractive substances formedicinal products for human use, including active substances intended for export. There has been no change to the corresponding guidance text for good manufacturing practice for active substances in Part II as aresult of this regulation.
GuidelinesonprinciplesofGoodDistribution Practice of active substances for medicinal products for human use (2015/C 95/01).
These guidelines provide stand-alone guidance on Good Distribution Practice (GDP) for manufacturers, importers and distributors of active substances for medicinal products for human use. These guidelines should be followed as of 21 September 2015.
Guidelines on setting health-based exposure limits for use in risk identiﬁcation in the manufacture of different medicinal products in shared facilities dealing with cross-contamination matters.
Guidelinesonthe formalisedriskassessmentfor ascertaining the appropriate GMP for excipients.

Changes on the horizon

Further new sections and revisions to the EC Guide to GMP are planned and are currently under discussion. These include:

Annex 1isbeing reviewed to take account of the principles in the ICH guidelines, to extend the underlying concepts to include new areas of technology and processing and to clarify areas that have been highlighted as ambiguous in the current version.
Annex 13 is being reviewed to take account of the changes from the Clinical Trials Regulation 536/2014 and the new Delegated Regulation on GMP for Investigational Medicinal Products.
Annex17isbeing amendedtoaddress thechanges from parametric release with afocus on therelease of terminally sterilised medicinalproductsto alignwiththe concepts of ICHQ8, Q9,Q10 andQ11 guidelines andthe QualityWorking Party’sguideline on real-timerelease testing. Apublic consultation took placefrom15September 2015 to 11 December 2015.
Annex 21 is being created to provide guidance to importers and different entities involved in importation activities of medicinal products due to theincreased complexityofsupply chains wheremanufacture of medicinal products for the European Economic Area market increasingly occurs outsideofthisterritory.A ConceptPaper wasatpublic consultation from 29 May to 29 August 2015 [and the text is due to be published for public consultation in late 2016].
The Commission is revising GMP for Advanced Therapy Medicinal Products, with the stated position that this will be self-standing guidance with no links to GMP for other medicinal products. This proposed new and self-standing guidance will require aconsequent revision of Annex 2 to remove references to ATMPs. An initial consultation was held from 23 July 2015 to 12 November 2015 and afurther consultation from 28 June 2016 to 26 September 2016.

The requirements introduced by the Falsiﬁed Medicines Directive for

subject of anew separate Regulation from the European Commission. Regulation (EU2016/161) sets out the practicalities of the safety features. These safety features are aunique identiﬁer (a 2D data matrix code and human readable information) which will be placed on medical products that can be scanned at ﬁxed points along the supply chain and tamper-evident features on the pack.The Regulation also sets out two lists, the list of prescription medicines that shall not bear the safety features and the list of non-prescription medicines that shall bear the safety features. The delegated regulation comes into force in the UK in February 2019. Also under the Delegated Regulation:

The Qualiﬁed Person is to ensure that the safety features have been afﬁxed.
Safety featuresare not to be removed or coveredunless the manufacturing authorisation holder veriﬁes that the medicinal product is authentic and has not been tampered with and that replacement safety features are equivalent and are applied in accordance with GMP.
Wholesale dealers are to verify that any medicinal products they receive are not falsiﬁed, by checking that any “safety features” used on the outer packaging of aproduct are intact.
Brokers and wholesale dealers are to record the batch numbers of, as a minimum, those products with safety features attached and for wholesale dealers to provide arecord of batch numbers when supplying those products to their customers.

The Orange Guide 2017

Iamvery pleased to report that this is the 10th edition of the Rules and Guidance for Pharmaceutical Manufacturers and Distributors known as the Orange Guide issued by MHRA. As with the previous publications this 10th edition continues to bring together existing and revised Commission-written material concerning the manufacture, importation, distribution andbrokering of humanmedicines andmattersrelating to the manufacture, importation and distribution of active substances.

While UK medicines legislation bears directly on activities in the UK, users of the guide now more than ever need to be fully aware of the original obligations set out in EU medicines legislation that affect them in the current changing landscape. Therefore, the “Titles” or sections of Directive 2001/83/EC,asamended, dealing with manufactureand wholesale distribution of products for human use, brokering ﬁnished medicinal products and provisions relating to the manufacture, importation and distribution of active substances remain in this edition.

In this 10th edition there are the revised GMP Annexes 15 and 16 and there are the new EU guidelines on setting health-based exposure limits in the manufacture of different medicinal products in shared facilities, the formalised risk assessment for ascertaining the appropriate GMP for excipients and the new the principles and guidelines of Good Manufactur-ing Practice for active substances for medicinal products for human use, including active substances intended for export. The new guidelines on principles of Good Distribution Practice of active substances are also incorporated. The EU Regulation on safety features for medicines is also partly reproduced prior to its transposition into UK medicines legislation by early 2019 together with the Commission Q&A. ACommission Q&A on the importation of active substances is included as well.

We have also incorporated anew section on MHRA Data Integrity deﬁnitions and guidance for Industry.The Guidance complements existing EU GMP guidance and should be read in conjunction with national medicines legislation and the GMP standards published in Eudralex volume 4. There is also anew section on matters relating to unlicensed medicines, GMP for excipients, guidance on revised Annex 16 of GMP and anew appendix on sources of useful information. Finally,updated sections have been provided for qualiﬁcation of suppliers and customers, parallel importation and parallel distribution, temperature control and monitoring of medicinal products and UK medicines legislation.

Although much of the text in this book is available in its original form in other places, including various websites, Iremain pleased that the Orange Guide continues to satisfy ademand for information in one authoritative and convenient place. In particular,the detailed Index to the Orange Guide at the end of the book, which conjoins the index created by MHRA for the EU GMPguideatreaders’requests,addsvalue and simpliﬁes the navigation of these complex documents. Readers are invited to suggest to MHRA further updates to the Index, for future improvements in navigation and cross-referencing.

For the 2017 version, we continue to have the entire Orange Guide available online, as part of “Medicines Complete” –asubscription-based database of leading medicines and healthcare references and in e-reader formats. Also available is aseparate updated GDP booklet for the wholesale dealing market. Ihope that this revised edition in its existing formats will continue to be useful.