09.01.2018 |

LOGFILE No. 01/2018 – Ask Our Experts – Part 2 – 4 GMP-Questions which might be of your interest

Ask Our Experts – Part 2

4 GMP-Questions which might be of your interest

7 minutes reading time

by Sabine Rabus

Being aware of all current aspects of GMP is quite a tough job. To clarify pending issues is an almost everyday business. The subscribers of our GMP Compliance Adviser, the world’s most comprehensive GMP online knowledge, have the unique opportunity to get answers to those GMP-questions that cannot be resolved within their company or that need additional expert advice. Since the introduction of the Ask Our Experts-Button time has shown that our service is not only well received but also extensively used by our customers.

For our LOGFILE readers we have compiled ten questions that reached us through the Ask Our Experts-Button. In LOGFILE 47/2017 we already published the first six questions. Today you’ll read another four question and answers. We believe they will be of interest to other GMP-professionals as well. Check them out!

7. Is it sufficient to label incoming material containers externally or in addition internally? Is it sufficient to label incoming material containers on the outside or additionally on the inside?

Starting material should be labelled by the supplier and should get an additional label after material income registration, sampling and release for manufacturing.

Regarding the second question, the material should be labelled on the primary as well as on the secondary packaging.

Relevant chapters in the GMP Compliance Adviser:

Chapter 11.H: Labelling of starting materials

Chapter 13.B.6: Labelling (packaging process)

Chapter 24.D.3 Labelling (incoming goods)
Chapter 16.D.3: Packaging and labelling (clinical samples)
Chapter 23.N: Packaging and labelling
Chapter C.14 9.3: Containers, packaging and labelling
Chapter C.6.13: Annex 13 - Labelling


8. It’s planned to install a new HVAC system in a tableting facility. The current ACPH in all areas are: Production >10 ACPH, Storage > 5 ACPH. What are the normal operating ranges for these areas in a non-sterile plant ISO 8?

Before answering the question just for clarification:

  • ISO 8 is not a clear and unique specification for a cleanroom in the pharmaceutical industry. It could be interpreted as a <Grade C in operation> or a <Grade D at rest> but only for particle load.
  • The ISO classification number does not include a separate limit for viable particles.

To answer the question, we will assume that you are talking about a grade C environment in operation.

Above all: determining an ACPH (air change per hour) is not suitable to classify the cleanliness of a cleanroom.

So, there is no “normal operating range” existing for a value of ACPH.

If you have a current ACPH value – check your existing qualification and/or monitoring data.

If you are far away from the recommended limits, the current ACPH could be reduced (saves a lot of running costs) under consideration of the thermal load.

Starting a new design, the ACPH has to be calculated as the highest value of

  1. the thermal load with a maximum allowed temperature difference of supply air to the specified room temperature (common value is a maximum of 6-8K)
  2. dilution or replacement of generated particles
    a. by personnel – that’s the biggest source
    b. by process – but particles of the tableting process are not to be seen as a contaminant – the airflow has to minimize operator contamination of the product and also to protect the operator from dust inhalation
  3. the maximum of allowed concentration of active substance in the air – determines if you can use recirculation-air or you have to use 100% outside air

    In addition you have to consider
  4. which air-filters you use (2 or 4 step of filtration and the filter class)
  5. situation and type of supply- and exhaust-air grids (high induction type should be avoided) – this is the biggest influence for the airflow in the cleanroom and determines the efficacy

So, no normal operating range for an ACPH is or could be determined without consideration of the above mentioned topics.

By our experience we would recommend the following:

• Start the concept/design with an ACPH of about 12-20

• The more details you can get about thermal load, particle generation of process and personnel the more the ACPH can be changed and optimized (ideally to 8-15)

A very good and recommended practice is to start the design with a CFD-Simulation and particle tracing (CFD – Computated Fluid Dynamics) for optimizing your airflow in quality and quantity. This could save a lot of money for later running an over-engineered system.

Relevant chapters in the GMP Compliance Adviser:

3.A Official requirements for premises
3.G Heating Ventilation Air Conditioning (HVAC)
3.J Pharma monitoring of HVAC systems


9. Do HEPA filters have an expiry date so the filter has to be replaced even if it passes a filter integrity test?

There is no maximum duration of use for HEPA filters to be found in the relevant GMP guidelines. The two criteria mentioned for a change of filter are leakage or pressure drop. As there is no legally binding value, the use of a filter more or less depends on company policies or is probably simply based on experience.

So, if your filter has passed the integrity test and no pressure drop or leakage was identified, it should be fine. Maybe you could get in touch with your supplier? He should be able to give you a more detailed information or recommendation regarding your special filter type.

For regulatory advice you could check out Chapter F.8 PIC/S PI 032-2 for sterile facilities or D.10 FDA aseptic guide in your GMP Compliance Adviser.

Relevant chapters in the GMP Compliance Adviser:

Chapter F.8: PIC/S PI 032-2
Chapter D.10: Guidance for Industry Sterile Drug Products Produced by Aseptic Processing


10. I would like to seek your opinion on in-house calibration by the unauthorized laboratory, (for example not certified for ISO17025 for the scope i.e. weighing balance calibration) but the calibration work is done by qualified personnel under the specified environment and traceable to the national standard.

What is your opinion? Are such practices allowed under the EU or US GMP regulatory environment?

To put it all in a nutshell:

Within the European Union and considering the convergence of the FDA to the EU, also for the FDA the practice you describe is not legally warranted.

The competence, impartiality and consistency of work of labs is regulated in DIN EN ISO/MEC 17025. Based on this ISO, the competence of a laboratory is retraced and verified. Calibration laboratories that meet these international standards are considered to be “competent”. A calibration certificate with logo of an accreditation body that is accredited according to this ISO is sufficient proof that the respective calibration data are being repatriated.

Furthermore, our expert says, that considering he has understood you question correctly, “a laboratory which is not accredited calibrates an external laboratory in a firm with qualified personnel and calibration data that can be repatriated” the scenario does not go together in his opinion. The reference instruments used for calibration must be calibrated by an accredited laboratory always. Otherwise the calibration is not considered sufficient in a GMP-conform environment and is not sufficient for documentation. It is not accurate enough!

But: Performance of calibrations within a company by internal personnel is quite in order, when the following is ensured:

  • an accredited laboratory has performed calibration of the reference instruments
  • the measurement inaccuracy of the measuring chain has to be available in house as logical rational
  • a mix up of intern/extern without a logical rational is prevented, as this would conflict with quality awareness

In addition, a PT100 with a temperature block has to be calibrated different form a balance on which APIs are being weighed. Therefore, it is recommended to always outsource balance calibration to an external company, simply only because of the handling of the calibration weights etc. This external company has to be accredited, e. g according to the above mentioned standard.

Please note: A revised DIN EN ISO/MEC 17025 entered into force on Dec 2017, with tighter requirements for laboratories.

Relevant chapters in the GMP Compliance Adviser:

Chapter 14.D: Laboratory instruments
Chapter 14.E: Calibration in the lab 
Chapter C.4.3: chapter 3 Premises and Equipment (EU-GMP) 
Chapter H.1: WHO GMP for pharmaceutical products 



Sabine Rabus
Maas & Peither AG – GMP Publishing
Schopfheim, Germany
E-Mail: sabine.rabus@gmp-publishing.com