GMP Compliance Adviser Update No. 2/2020

With this GMP Compliance Adviser UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

GMP in Practice

Chapter 3

3.J Qualification of premises and air handling technology

3.K Pharma monitoring of HVAC systems

Chapter 16 16.L Monitoring

GMP Regulations

Chapter C 

EU Directives and Guidelines

C.10.2  ICH Q12: Regulation (EU) 2017/746 of ­the ­European Parliament and­ of­ the­ Council (EU IVDR) including Corrigendum 2, published on 27 December 2019

C.17 ATMPs: Questions and answers on the exemption from batch controls carried out on ATMPs imported into the European Union from a third country

C.18 ATMPs: Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products


GMP in Practice

Chapter 3.J Qualification of premises and air handling technology

Production premises and their associated utilities and infrastructure, including air handling units, are of essential significance to the quality of pharmaceutical products. Thus, their qualification is a requirement.

The qualification should be limited to aspects and parameters which have significant impact to product and personal safety according to the risk assessment; for all others, which are required for proper technical functioning of the premises and air handling units, technical acceptance testing according to GEP is sufficient.

The basis for demanding qualification projects is provided by Qualification Master Plan derived from the User Requirement Specification. One differentiates the process into four consecutive qualification stages. The conclusion of each qualification stage is documented via a qualification report. The scope of the qualification activities depends on the complexity of the construction project and the requirements derived from the product characteristics, for example and the air purity. Comprehensive checklists are meant to help define the qualification effort in sufficient scope and detail.

The equipment, plants and operating systems shall be evaluated at a sufficient frequency in order to confirm its qualified status. The possibility should be evaluated that minor changes occur over time. Equipment, facilities, plants and systems are to be evaluated at sufficient intervals in order to confirm their qualified status. The possibility that minor changes occur over time should be considered. If there be a need for re-qualification and this is performed at certain temporal intervals, these intervals are to be justified and the success criteria for re-qualification are to be defined.

The chapter also includes a protocol template that shows which contents are to be inspected during the IQ/OQ of an AHU and how processing can be simplified by means of a clearly arranged form. The protocol template is also available as an editable Word file. (Harald Flechl)

Chapter 3.K Pharma monitoring of HVAC systems

The purpose of pharma monitoring of the HVAC system is collection, recording and storage of data relevant for the quality of medicinal products. Such data frequently will have to be incorporated into their batch documentation.

Physical data requiring continuous or frequent recording are, at least in the case of premises for sophisticated production tasks, collected, processed and stored electronically – and this for an extended period of time well beyond the expiry dates of the products. Complementary physical and, above all, microbiological data, on the other hand, are collected and recorded manually.

Both sets of data, i.e. those from computerized monitoring and those obtained through manual data compilation, should periodically be submitted to a trend analysis. In order to discover excursions from the specified data range and developing problems at an early stage and to be able to act upon them in time, alert and action limits should be set for the physical monitoring parameters. Exceeding these limits should trigger alarms. The automatic and inextinguishable registration of such alarms is an important additional task of computerized pharma monitoring systems. (Harald Flechl)

Chapter 16.L Monitoring

Monitoring temperature during transport is imperative above all in qualification and validation phases, in order to make certain that the necessary transport conditions are met.

In routine transports as well, at least random checks are advisable or possibly comprehensive monitoring, depending on the criticality of the transport. In addition to temperature, other data relevant to quality can also be gathered and recorded here.

Mobile temperature loggers can be used for monitoring. They are inexpensive and versatile in terms of application; however, the data is not available until after they are read out. Therefore, telematics systems are more advantageous as they enable direct data transmission and evaluation. Furthermore, telematics systems contain additional functionalities such as locating functions, gathering vehicle data, personnel and communications management. RFID technology, which has been recommended by the FDA, is less suitable for temperature monitoring, but is used instead to track shipments in keeping with supply chain integrity.

Alarm systems must be designed to cause excursions above or below the specified temperature range to generate an alarm that is directly displayed in the driver's cab and, depending on the configuration of the alarm plan, an alert is also forwarded to the carrier and/or dispatcher.

Monitoring systems can be validated in accordance with the V-model described in GAMP 5. Using this model, validation can be performed in a GMP-compliant and efficient way. Risk analysis plays an important role here. (Christoph Frick, PhD, Rainer Röcker, Nicola Spiggelkötter, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.10.2 Regulation (EU) 2017/746 of ­the ­European Parliament and­ of­ the­ Council (EU IVDR) including the second Corrigendum published on 27 December 2019

The second corrigendum to Regulation (EU) 2017/746 includes minor editorial corrections and additions/corrections relating to specific article references to Directive 98/79/EC in

  • the first subparagraph of Article 83(1)
  • Article 110(8)
  • point (b) of the first paragraph of Article 112
  • Article 113(3), point (a)
  • Annex III, Section 1, point (b), fifth bullet point
  • Annex VIII, Section 2.2, introductory phrase

C.17 ATMPs: Questions and answers on the exemption from batch controls carried out on ATMPs imported into the European Union from a third country

The Q&A explains when exemptions from batch re-testing of imported AMTPs are permitted.

Four questions and their answers clarify

  • the responsibilities of the Qualified Person in the event of re-testing
  • which exemptions apply
  • which data have to be submitted, and
  • the responsibilities of the Qualified Person in case of an exemption.

C.18 ATMPs: Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products

Six pairs of questions and answers explain a possible pathway for the administration of out-of-specification (OOS) batches that have already been granted a marketing authorisation.

Answers are given on the following questions:

  • What is the administrational pathway for OOS batches?
  • Who should be notified and when?
  • Are National Competent Authorities involved?
  • How should the manufacturer/importer/MAH notify the EMA of the OOS batch(es)?
  • What are the obligations or expectations the manufacturer/importer/MAH should follow?
  • What information should be provided to the patient?

Interested in using the GMP Compliance Adviser?

More information & order: GMP Compliance Adviser