This summary review of GMP documents published in 2018 provides an overview on developments in

important international legislation and regulations.

FDA: Guidance on Data Integrity and Compliance with Drug CGMP, December
2018
On 13 December 2018, the US FDA published the final guidance for industry on data integrity. The 17-
page document is structured into 18 Q&A’s and describes the role of data integrity in CGMP for drugs,
as required in 21 CFR parts 210, 211, and 212. Required is a risk-based approach with an effective
strategy for collecting reliable and accurate process data based on process knowledge and empirical
values.

 GMP News
 Guidance

EU/US: Q&A to MRA on Inspections, December 2018

On 1 June 2018, the EMA published a corresponding Q&A document on the Mutual Recognition
Agreement (MRA) between the EU and the United States. The 10 questions and answers reflect the
current state of the agreement and is updated regularly. The document was last updated on 1
December 2018.

 GMP News
 Q&A

EMA: Q&A to Safety Features for Medicinal Products, November 2018

The 28-page document setting out frequently asked Q&As regarding the implementation of the rules
on the safety features for medicinal products for human use has been revised. As of November 2018, it
is available in Version 12.

The changes compared to the superseded version regard questions 1.20 and 2.21.

1.20 If a pack bearing the safety features is lawfully opened (e.g. by parallel traders/manufacturers
replacing the leaflet under the supervision of national competent authorities), can it be resealed (e.g.
by applying a new ATD on top of the old, broken ATD)?

2.21 Is it acceptable to use stickers to place the unique identifier on the outer/immediate packaging?

 GMP News
 Q&A

www.gmp-publishing.com
© 2019 Maas & Peither AG – GMP Publishing, Schopfheim, all rights reserved. page 1 of 6
GMP Compliance Adviser Member Extras / January 2019 GMP Regulations Report 2018

EMA: Draft Guideline on the Quality of Water for Pharmaceutical Use,

November 2018
The draft published on 15 November 2018, is open for public consultation until 15 May 2019.

This 10-page document, once final, will replace the current “Note for guidance on quality of water for
pharmaceutical use” from 2002 and the “CPMP Position Statement on the Quality of Water used in the
production of vaccines for parenteral use".

 GMP News
 Draft guidance

ICH: Revised Q3C(R7) on Impurities: Guideline for Residual Solvents, October

2018
The revised ICH Q3C(R7) guideline along with three Q3C Support Documents was published on October
25, with an error correction of the Permitted Daily Exposure (PDE) for ethylenglycol.

• Ethylenglycol is now listed with a new PDE of 3.1 mg/day and a concentration limit of
310 ppm (before: 6.2 mg/day and 620 ppm).

Information on the drafting process of the next version (ICH Q3C(R8)) was also announced. The
next update will include PDE levels for three solvents

• 2-methyltetrahydrofuran
• cyclopentylmethylether and
• tert-butanol.

A final version of Revision 8 can be expected by the end of 2019.

 GMP News
 ICH Q3C(R7)

CDSCO India: Draft Guideline on GDP for Pharmaceuticals, October 2018

The CDSCO (Central Drugs Standard Control Organization) has published a 21-page draft on GDP for
pharmaceutical products.

The objective of the guidelines is to ensure the quality and identity of pharmaceutical products during
all aspects of the distribution process. These aspects include e.g. procurement, purchasing, storage,
distribution, transportation, documentation and record-keeping practices.

The draft covers the topics well known from other GDP guidelines.

 GMP News
 CDSCO: GDP-Draft Guideline

www.gmp-publishing.com
© 2019 Maas & Peither AG – GMP Publishing, Schopfheim, all rights reserved. page 2 of 6
GMP Compliance Adviser Member Extras / January 2019 GMP Regulations Report 2018

EC: New Annex 2 for Manufacturing Biological Products, June 2018

The new version of Annex 2 "Manufacture of Biological active substances and Medicinal Products for
Human Use" has been in operation since 26 June 2018.

Annex 2 is no longer applicable to Advanced Therapy Medicinal Products to which now applies the
Commission guideline on Good Manufacturing Practice for Advanced Therapy Medicinal Products. The
separate guideline on ATMPs is listed under Part IV of Eudralex Volume 4 and entered into force on 22
May 2018.

 GMP News
 Eudralex Volume 4, Annex 2

EC: New Annex 17 on Real Time Release Testing and Parametric Release, June
2018
The final version is newly entitled Annex 17: Real Time Release Testing and Parametric Release. The 8-
page document came into force on 26 December 2018 and replaced the preceding version of the year
2002.

Since then, there have been significant changes in GMP consequent to the adoption of the ICH Q8 -
Q11 guidelines and revisions within the EU GMP Guide or the EMA Guideline on RTRT in 2012.
Advances in the application of process analytical technology (PAT), quality by design (QbD) and quality
risk management (QRM) principles to pharmaceutical development and manufacturing have shown
that appropriate combination of process controls together with timely monitoring and verification of
pre-established material attributes provide greater assurance of product quality than end-product
testing alone.

 GMP News
 Eudralex Volume 4, Annex 17

EMA: Update of Two Brexit Guidance Documents, June 2018

The European Medicines Agency (EMA) published two documents to assist pharmaceutical
manufacturers in preparing for Brexit:

• Revision 2 of its “Practical guidance for procedures related to Brexit for medicinal products for
marketing authorisation holders (MAH)”
• Q&A document “Q&As related to the UK’s withdrawal from the EU with regard to the
medicinal products for human and veterinary use within the framework of the Centralised
Procedure” (Revision 3).

For the Practical Guidance EMA has added 14 new questions (marked as “NEW”) including who
companies should contact at EMA with Brexit-related inquiries, how to consider national scientific
advice from UK competent authorities and how to transfer orphan designations from UK-based
sponsors to those based in the European Economic Area.

The Q&A document provides procedural and practical guidance regarding submission of changes and

www.gmp-publishing.com
© 2019 Maas & Peither AG – GMP Publishing, Schopfheim, all rights reserved. page 3 of 6
GMP Compliance Adviser Member Extras / January 2019 GMP Regulations Report 2018

related fees. Seven new questions were added and some earlier answers updated (marked as “NEW”).
A template containing a standard statement for change of applicant due to Brexit is also provided.

 GMP News
 Practical Guidance
 Q&A

PIC/S: New Guidance Documents, June 2018

The following PIC/S guidance documents have been published:

• PIC/S Aide-Memoire on “Cross-Contamination in Shared Facilities” (PI 043-1).

• PIC/S Guidelines on the formalised risk assessment for ascertaining the appropriate good
manufacturing practice for excipients of medicinal products for human use (PI 045-1);
• PIC/S Guideline on setting health based exposure limits for use in risk identification in the
manufacture of different medicinal products in shared facilities (PI 046-1);
• PIC/S Guidelines on the principles of GDP for active substances for medicinal products for
human use (PI 047-1)
• The PIC/S GMP Guide (PE 009-14) has been revised according to the EU GMP Guide and is now
in alignment with the principles of QRM (Revision of Chapters 3, 5, 8 and Annex 17).

All documents are listed on the “Publications” page of the PIC/S and entered into force on 1 July 2018.

 GMP News
 PIC/S Publications

WHO: 52nd Technical Report Series No.1010, June 2018

With the publication of the 52nd TRS No. 1010, eleven guidelines were adopted and recommended for
use.

In the area of Quality Assurance – GMP this concerns the following documents:

• Guidelines on good herbal processing practices for herbal medicines (Annex 1)

• Good manufacturing practices for herbal medicines (revision) (Annex 2)
• Guidelines on good manufacturing practices for heating, ventilation and air-conditioning
systems (revision) (Annex 8)
• Guidance on good practices for desk assessment of compliance with good manufacturing
practices, good laboratory practices and good clinical practices for medical products regulatory
decisions (Annex 9)
• Stability testing of active pharmaceutical ingredients and finished pharmaceutical products
(revision) (Annex 10)

 GMP News
 52nd TRS1010, WHO

www.gmp-publishing.com
© 2019 Maas & Peither AG – GMP Publishing, Schopfheim, all rights reserved. page 4 of 6
GMP Compliance Adviser Member Extras / January 2019 GMP Regulations Report 2018

EMA: Q&A on Health-Based Exposure Limits, April 2018

On 30 April 2018, the EMA published the final revised version of the Q&A document which covers 13
questions and answers related to the “Guideline on setting health based exposure limits for use in risk
identification in the manufacture of different medicinal products in shared facilities”.

 GMP News
 Q&A

WHO: Three Draft Documents for Commentation, March 2018

The WHO has released three interesting documents on its website for public comments:

• A 4-page inquiry regarding production of “Water for Injection” (March 2018)

• A 20-page draft on GMP for HVAC systems for non-sterile pharmaceutical dosage forms: Part 2;
Interpretation of Part 1 – GMP for HVAC systems (February 2018)
• An 11-page draft on Validation Appendix 6, Guidelines on Qualification

 GMP News

MHRA: „GxP Data Integrity Guidance and Definitions“, March, 2018

The British MHRA published the final version of its GxP data integrity guide on March 9, 2018.

There has been significant stakeholder interest in the development of the guide. More than 1300
comments were received and taken into consideration. The GXP data integrity guidance has a high
degree of alignment with documents published by other regulators such as PIC/S, WHO, OECD
(guidance and advisory documents on GLP) and EMA. Those documents are also listed as references.

 GMP News
 GXP data integrity guidance

MHRA: Out of Specification Guidance

The MHRA updated its interesting guidance on how to handle OOS results. The guidance – which is in
form of a PowerPoint presentation – offers a stepwise approach on what should be considered at each
stage of an investigation.

 GMP News
 OOS-guidance

www.gmp-publishing.com
© 2019 Maas & Peither AG – GMP Publishing, Schopfheim, all rights reserved. page 5 of 6
GMP Compliance Adviser Member Extras / January 2019 GMP Regulations Report 2018

EC/EMA: New Guidelines on ATMPs, February 2018

The EMA released two documents for ATMPs (Advanced Therapy Medicinal Products) on 1 February
2018. Alongside the updated advice document, EMA also released a new draft guideline on follow-up
safety and efficacy requirements and risk management for ATMPs.

• Procedural Advice on the Evaluation of ATMPs

• Draft Guideline on Safety and Efficacy follow-up and Risk Management of Advanced Therapy
Medicinal Products.

 GMP News
 Procedural Advice on the Evaluation of ATMPs
 Draft guideline for ATMPS

Swissmedic: Authorisation of Biosimilars and Q&A Document, January 2018

Swissmedic has announced that the foreign comparator product with a biosimilar for the main studies
can also originate from the USA, while that for supplementary studies can now also originate from
Canada.
Until then Swissmedic had only accepted the reference product from Switzerland or a product from the
EU. For supplementary studies, comparator products from Japan have also been accepted.

An Environmental Risk Assessment (ERA) is compulsatory for biosimilar submission to Swissmedic.

The guidance document “Authorisation of Biosimilars” as well as the corresponding Q&As were
updated accordingly.

 GMP News
 Guidance
 Q&A

www.gmp-publishing.com
© 2019 Maas & Peither AG – GMP Publishing, Schopfheim, all rights reserved. page 6 of 6