MHRA’s Guidance for Software as a Medical Device (including Apps)


The British MHRA (Medicines and Healthcare Products Regulatory Agency) has published a guidance for developers of “software as a medical device”  = “stand-alone software”. The text also expressly addresses “apps”. Get the details here.–including-Apps-_8308,8394,9058,9051,Z-COVM_n.html

Whereas in the pharmaceutical business software plays a role in the manufacture of products, it can also act as two parts in the medical device business – one in the manufacture of a device and one as a medical device as such – i.e. software as a medical device. The British Health Authority – MHRA – has published a current guidance on software as a medical device, also called stand-alone software, intended for developers of such software. This guidance also addresses the increasingly encountered topic “apps”. The text doesn’t cover software that is part of a medical device, e.g. software that controls a CT scanner.

The guidance itself is very short and divided into 6 main chapters:

  • Introduction
  • Key points and existing guidance
  • Software applications (apps)
  • Telehealth and telecare
  • General requirements
  • Specific software considerations

The topic software application (apps) is extensively described. If apps fulfil the definitions of a medical device, MHRA regulations will apply and they will undergo a conformity assessment. The following keywords should help the MHRA determinate whether the apps are a medical device or not:

  • amplify
  • analysis
  • interpret
  • alarms
  • calculates
  • controls
  • converts
  • detects
  • diagnose
  • measures
  • monitors

Furthermore, the guidance provides some support on which apps can be basically categorised as medical devices and which not:

  • Decision support or decision making software that applies some form of automated reasoning, such as a simple calculation, a decision support algorithm or a more complex series of calculations, e.g. dose calculations, symptom tracking, clinicians guides. These are the types of software most likely to fall within the scope of the medical devices directives
  • Apps acting as accessories to medical devices such as in the measurement of temperature, heart rate, blood pressure and blood sugars could be a medical device as are programmers for prosthetics
  • Software that monitors a patient and collects information entered by the user, measured automatically by the app or collected by a point of care device may qualify as a medical device if the output affects the treatment of an individual
  • Software that provides general information but does not provide personalised advice, although it may be targeted to a particular user group, is unlikely to be considered a medical device
  • Software that is used to book an appointment, request a prescription or have a virtual consultation is also unlikely to be considered a medical device if it only has an administrative function.

In addition, the guidance refers to a range of other documents and European Guidelines on medical devices which provide other important information.

Source: MHRA – Guidance on medical device stand-alone software (including apps)

Questions and Answers on the Topic “Pharmaceutical Water”


In the following News, you will find questions on pharmaceutical water preparation and distribution frequently asked during our courses, as well as their respective answers. Read more here.,8427,8428,8526,Z-PEM_n.html

During our courses and conferences participants quite frequently raise questions on pharmaceutical water preparation and distribution. Therefore following you will find some of these questions and their respective answers.  

Question 1:  Which concentrations of ozone are required in water systems?

The technical literature delivers different information about the ozone concentrations in water systems: e.g. ISPE Baseline Water and Steam: 0.02 ppm – 0.2 ppm; Collentro, Pharmaceutical Water: 0.2 ppm – 0.5 ppm and W.Setz, Ciba-Geigy 1990: max 0.04 ppm, for sanitisation 0.05 ppm.
The indications provided by the ISPE Baseline refer to the concentration required to prevent microbial growth. One can thus assume that a concentration of 20 ppb ozone can prevent any growth.

If systemic protection is desired i.e. the constant presence of ozone in the water, lower ozone values are sufficient.
In practice, approx. 0.02 to 0.05 ppm should be sufficient for Aqua Purificata. For sanitisation, it naturally depends on the sanitation time intervals – daily or weekly. Finally, the required ozone concentration for the system should be determined within the framework of the validation for the whole system.

Question 2: How many ozone measurement points should be available in the water system?

If ozone is used for the sanitisation of the distribution system, the effect should also be proven by means of – indirectly – the determination of the KBE values on the one hand, and on the second hand through the proof that the ozone concentration is measured at the appropriate points in the water system. For this purpose, the ISPE Baseline mentions at least 3 measurement points:

  • In the storage tank
  • After the UV system
  • In the return flow

The measurement in the storage tank shows that the concentration is sufficient during the permanent ozonisation. After the UV system, a measurement is done to assure destruction of the ozone. The post-use point in the return flow of the pipeline system is measured to prove that the ozone concentration is sufficient during sanitisation.

Question 3: Is there – from a GMP point of view – a preferred sanitisation method?

Basically, the following three sanitisation procedures are used today:

  • Hot water sanitisation
  • Sanitisation with steam
  • Chemical sanitisation

The FDA, as well as the ISPE in its Baseline – are in favour of thermal sanitisation with steam. The Guidance for Industry: Sterile drug products produced by aseptic processing Prepared by Task Force (Japan) contains the following note:
Since water for injection needs to be microbiologically pure, the equipment used for its production should be capable of withstanding periodic sterilization with pure steam at temperatures over 121°C for a given length of time. If steam sterilization is not possible because of low heat tolerance, an alternative sterilization or sanitization procedure (e.g., hot water or chemical agents) should be used for the equipment.”
GMP doesn’t specify any method. According to the state of the art, one should prefer sanitisation with steam.

Question 4: Is cold storage allowed in WFI systems?

For WFI and purified water, different temperatures are used. WFI is usually stored under heat.
In FDA’s Guide to Inspections of High purity Water Systems you can find two indications of temperatures which are actually contradictory. The first temperature interval is described under “System Design”. “The fist chapter basically states under “System Design” that it is recognized that hot water systems (here to understand as 65 to 80°C systems) are self sanitizing. Another temperature interval is indicated in the chapter “Piping”. This concretely means here that the Guide applies to hot 75 – 80°C circulating systems. These indications are in connection with the 6D rule:
One common problem with piping is that of “dead-legs”. The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 – 80°C circulating systems.”
It follows from the above that cold systems for WFI actually don’t comply with the requirements. Under these circumstances, it is likely that at least the FDA doesn’t accept cold WFI systems.

If appropriate measures (system design and sanitisation measures) can ensure that microbial growth is prevented, cold storage could basically be used. Different limits for cold storage can be found in guidelines and standards (Wallhäuser: 4°C;  ISPE: 4° to 10°C). A sanitisation concept for cold storage determined within validation is imperative and should also consider the increased high-risk of bio film formation.

Question 5: Are sterilizing filters permitted in water systems?

The answer to that question requires the examination of the legal provisions and the standards and guidelines on the topic “Water”. The EU GMP Guide describes in a few points the requirements for facilities and equipment. Relating to the sterilizing filters, the following indications may be authorised:

  • EU GMP 3.38: “Equipment should be installed in such a way as to prevent any risk of error or contamination.”
  • EU GMP 3.39: “Production equipment should not present any hazard to the products.”
  • EU GMP 3.36: “Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned.”
  • EU GMP Annex 1: “Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality.”

In almost all guidelines, references are made to sterilizing filters. As an example, see the following statement from a Japanese guideline: Sterile drug products produced by aseptic processing (Japan 2006)

“As a rule, sterilizing filters should not be placed at water use points since the filters could mask microbiological contamination in the water system. Endotoxins could also be released from dead microorganisms retained in the filters. If the use of filters is unavoidable, the interval of replacement should be based on validation results.”

In this Japanese document, the position to filters is obvious: no sterilizing filters should normally be used. Yet, there can definitely be exceptions. The filters shouldn’t serve for masking too high KBE values. Finally, one should justify the use of such a filter.

EU Commission publishes long-awaited EU GMP Guide Chapters 3 and 5


The EU Commission has published the long-awaited, revised chapters 3 and 5 of the EU GMP Guide. The change focuses on the prevention of cross-contamination as well as on the statement concerning the need for dedicated facilities. Continue reading.,8427,8526,Z-PEM_n.html

The EU Commission had published its first draft of the chapter 3 “Premises and Equipment” and 5 “Production” for comments in early 2013 (see news from 04/12/2013). The content concerns the measures for avoiding cross-contamination and the regulation relative to which products have to be produced in dedicated facilities.

The mention of specific products for which a dedication is required – as provided in the currently valid version of chapter 3 – is missing in the now published version. The quality risk management approach is maintained. Also remaining are the exceptions where dedication is required – which are:

  • The risk cannot be adequately controlled by operational and/ or technical measures, or
  • Scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta lactams) [Note: the draft version was mentioning missing thresholds], or
  • Relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.

But the main difference to last year’s draft version is that there is no referencing for how the repeatedly mentioned toxicological assessment has to be done. The last draft for this purpose referenced the EMA Guideline (setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities), which is still in draft stage and is subject of controversial discussions. This of course creates new liberties. At the same time, though, it generates just as much uncertainty what such a toxicological assessment has to look like after all to be accepted by the authority. Chapter 5.20 provides some indications with regard to how the decision process has to be done risk-based and scientifically formal. Concrete information on the toxicological risk classification or derivation of the limit cannot be found here.

To find the new Chapters valid from 1 March 2015 please see