GMP Compliance Adviser Update No. 7/2018

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

4.E Technical documentation
4.G Maintenance
24.E Qualification of a cold-storage facility
24.F Standard storage at 15-25°C? A case study challenging conventional limits

GMP Regulations

D.1.1 21 CFR Part 210
D.1.2 21 CFR Part 211
D.1.3 21 CFR Part 11
D.1.4 21 CFR Part 820
D.1.5 21 CFR Part 4
D.1.6 21 CFR Part 600
D.1.7 21 CFR Part 606
D.1.8 21 CFR Part 680
D.1.9 21 CFR Part 601

GMP in Practice

Chapter 4 Facilities and equipment

4.E Technical documentation

Without technical documentation it is not possible to qualify, calibrate, operate, repair or maintain machinery and equipment. It is recommended to apply the same standards when utilising technical documentation as for the pharmaceutical manufacturing and testing documentation.

It is not sufficient to just introduce systems and leave them to manage themselves. Technical documentation files need to be updated regularly as part of change management procedures. What is decisive for its success is whether the organization buys into the system, includes it into its regular operations and supports its development. In machine, room and system logbooks all the tasks executed are to be documented in chronological order.

As part of Industry 4.0, technical documentation will also change. New technologies should make it possible to improve the interconnections of information resources and to access them more easily. (Ruven Brandes)

4.G Maintenance

Maintenance encompasses a range of activities including inspection, repairs and preventive maintenance.

One of the primary purposes of a maintenance programme is the assurance of the need-specific machine and plant availability while ensuring minimal product risk. The effectiveness of the maintenance programme depends on the selection of the optimal time point for the maintenance activities. To solve the optimisation problem, there are different fundamental approaches. These approaches are known as maintenance strategies.

A comprehensive maintenance concept should include an optimal mixture of the run-to-failure approach, preventive maintenance, condition-based maintenance and predictive maintenance. A special position is held by risk-based maintenance, whereby decisions about the proper maintenance strategy are taken based on the quality and business risks. When properly established, this type of maintenance programme is very effective and it reduces the maintenance costs.

The goal of a GMP-compliant maintenance programme is to minimize the occurrence of failures and thus to stabilise the course of manufacturing and packaging processes.

The potential benefit of using an electronic maintenance management system should be weighed against the cost-benefit ratio and if appropriate, should be introduced in a controlled manner.

Effective organisation and standardised processes simplify the reaction in Operations to malfunctions and breakdowns and to take the appropriate actions. With the help of modern sensor technology, the precise monitoring of machine status is possible. Deviations from target result in the automatic transmission of messages to the maintenance team.

Standardised error messages and records of failure causes make it possible to identify failures in advance with the possibility to stabilise the utilisation of the machine by using analyses reducing the failure rate. (Ruven Brandes)

Chapter 24 Storage and Transportation

24.E Qualification of a cold-storage facility

Regardless of whether a newly built cold-storage facility or an existing one is undergoing qualification, safe storage at 2–8°C is essential for preserving the effectiveness and safety of medicinal products that require cold storage. For this reason, some mandatory requirements have to be met:

  • air inlet temperature not below 2°C
  • maintenance of the stipulated 2–8°C in all areas using a uniform air flow
  • a qualified monitoring system
  • a secure alarm system
  • deviation and change management
  • corresponding SOPs on "safeguarding the cooling cycle"
  • trained personnel

Careful planning and excellent communication between all persons involved are important prerequisites for a successful qualification.

The qualification of a new cold-storage facility can be carried out in accordance with the V-model. Risk analysis is a key factor. Essential tests such as temperature mapping and testing of redundancy and the alarm system can be carried out during the SAT. The monitoring system, i.e. the continuous measurement and documentation of temperature, is based on the results of temperature mapping.

In accordance with GDP requirements, cold-storage facilities that are already in operation but have not yet been qualified must also undergo qualification. As a minimum requirement, a PQ should be carried out that includes temperature mapping. The required qualification steps and their content must be adapted accordingly. Risk analysis is, once again, a key factor when this is done.

In order to maintain the qualified status, regular maintenance and calibration are required along with the implementation of a change and deviation management system. (Christoph Frick, PhD)

24.F Standard storage at 15–25°C? A case study challenging conventional limits

Whether the guidelines of the WHO, ICH and EMA that deal with the storage of medicinal products, nor the GDP Guidelines and the European Pharmacopoeia do prescribe a mandatory temperature range of 15–25 °C for the storage and transportation of standard medicinal products.

Nevertheless, storage at "room temperature" or at "15–25 °C" is widely understood to be necessary. To maintain this temperature range, however, energy must be used for heating; budgets and the environment are needlessly burdened.

For this reason, a case study was carried out to examine whether a broadening of the temperature range to 9–25 °C would negatively affect the quality and safety of standard medicinal products and medical devices.

Data was generated that shows a reduction of the lower temperature limit to 9 °C with a warning limit of 10 °C does not have a negative effect on the products that were examined.

Measures were subsequently taken so that products can be stored at 9–25 °C in the future. They included changing the warning and alarm limits, the installation of additional temperature sensors and the inclusion of new products in the existing risk analysis to determine the required storage conditions.

The temperature range of 9–25 °C instead of 15–25 °C should also be applied to the transportation of medicinal products. In this case, a short-term deviation from 2–30 °C for up to 12 hours during transportation will not affect the quality of preparations. (Christoph Frick, PhD)

GMP Regulations

Chapter D USA: CFR and FDA Guidelines


The Code of Federal Regulations is subject to an annual revision. With the current Update of the GMP Compliance Adviser we provide the actual versions as of April 1, 2018.

The dates of the following CFRs have been updated without any further amendments:

  • D.1.1: 21 CFR 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs
  • D.1.2: 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals
  • D.1.3: 21 CFR 11 Electronic Records; Electronic Signatures
  • D.1.4: 21 CFR 820 Quality System Regulation
  • D.1.5: 21 CFR 4 Regulation of Combination Products
  • D.1.6: 21 CFR 600 Biological Products
  • D.1.7: 21 CFR 606 Current Good Manufacturing Practice for Blood and Blood Components
  • D.1.8: 21 CFR 680 Additional Standards for Miscellaneous Products
  • D.1.9: 21 CFR 601 Licensing Service

Interested in using the GMP Compliance Adviser?

>>> More information & order: GMP Compliance Adviser