PIC/S GMP PE009-17

PIC/S GMP Guide PE 009-17 Quietly Published

On 21 June 2023, PIC/S quietly published version 17 of its Guide to Good Manufacturing Practice for Medicinal Products (‘PIC/S GMP Guide’), PE 009-17 effective 25 August 2023.

The sole substantive change being introduced with PE 009-17 is inclusion of the revised Annex 1 (Manufacture of sterile medicinal products), which was published in September 2022, after undergoing revision which was extensive in terms of content, effort, and time. The date on which version 17 of the PIC/S GMP Guide comes into force coincides with that of the identical updated Annex 1 in Eudralex Volume 4 (EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use).

Includes / Revises Annex 1: Key Changes

Because the introduction of revision 17 of the PIC/S GMP Guide is effectively the formal introduction of the revised Annex 1, any discussion of revision 17’s changes is effectively discussion of the changes of Annex 1, which PIC/S published in September 2022. PharmOut was keenly following the revised Annex 1 throughout its tortuous eight-year development, and has kept industry abreast of the changes — e.g. through posts like this and through public training sessions — over this time.

As a complete, ground-up re-write, the revised Annex 1 being formalised in PE 009-17 is essentially unrecognisable in comparison with previous iterations. A brief survey of the raw numbers illustrates the extent of the changes:

  • In PE 009-16, Annex 1 had 127 clauses spanning 18 pages; in PE 009-17, Annex 1 has 294 clauses, which are frequently more comprehensive than those in PE 009-16, increasing the page count to 66 pages;
  • Of the 127 clauses in Annex 1 of PE 009-16, only approximately 40 are effectively unchanged in PE 009-17, and at least 14 have been removed altogether; and
  • Of the 294 clauses in PE 009-17, more than 100 are entirely new, with no direct corresponding clause in PE 009-16.

Unsurprisingly, the changes implemented with the introduction of PE 009-17’s revised Annex 1 cover an extensive range of activities for the GMP-compliant manufacture of sterile products. New or revised requirements include:

  • Enhanced emphasis on Quality Risk Management (QRM) for the identification and mitigation of risks to product quality, including the use of risk assessment, risk control, and risk monitoring to identify and address potential risks to product quality;
  • New requirements for closed systems, including requirements for the design, qualification, and use of closed systems, as well as for the monitoring of closed systems for leaks and other potential problems;
  • Updated requirements for environmental monitoring, including requirements for the frequency and methods of environmental monitoring, as well as for the interpretation of environmental monitoring data;
  • New requirements for process validation, including requirements for the design, execution, and documentation of process validation studies; and
  • Updated requirements for documentation, including requirements for the format, content, and storage of documentation.

It is evident even from this brief summary that keeping oneself properly abreast of the changes requires more than simply skim-reading PE 009-17’s Annex 1 over a quick cup of coffee.

Thankfully for industry, PharmOut’s PIC/S GMP Training Course, and GMP eLearning for PIC/S GMP topics generally and for Annex 1 specifically, are constantly being updated to maintain currency with GMP developments such as this.

Thinking that you are safe from the burden of considering and complying with all of these changes, because you aren’t involved with the manufacture of sterile goods for a territory where the revised Annex 1 is imminently coming into force? Don’t be too complacent: even in non-sterile manufacturing environments it is often informally expected that the principles of Annex 1 will be followed; and in keeping with PIC/S’ expressed aim to harmonise global GMP standards and inspection procedures, even in territories that are not introducing the revised Annex 1 (either in the PIC/S GMP Guide or Eudralex Volume 4) in August 2023, it is only a matter of time until the principles of the revised Annex 1 are formally adopted.

Surprisingly – ICH Q9(R1) Not Incorporated IN Annex 20

From the foregoing discussion, it is clear that what has been included in PE 009-17 is the revised Annex 1, which was published in September 2022. What has not been included in PE 009-17, however, is a revision to Annex 20 (Quality risk management) to include principles now advocated in ICH Harmonised Guideline Quality Risk Management Q9(R1), which was adopted on 18 January 2023.

The key changes that were introduced with Q9(R1) were: scaling of the formality and rigour of quality risk management activities; a general re-framing of risk management tools from general “risk management” to the more focussed “quality risk management”; and the enumeration of considerations for the effective management of quality risks to the product supply chain.

Despite PE 009-17 only including changes to its Annex 1, this does not mean that the requirements for, and the importance of, risk management in sterile manufacturing have remained static. To judge again from raw numbers: the word “risk” appears in PE 009-17 a total of 762 times, increasing from 653 times in PE 009-16. It is therefore evident that for medicines manufacture, quality risk management continues to increase in importance.

PharmOut can, of course, assist people who wish to learn more about this important aspect of manufacturing medicines, for example through our GMP Quality Risk Management – ICH Q9(R1) Training Course and our Annex 20 Quality Risk Management & ICH Q9(R1) eLearning course.

Australian TGA Adoption of Revised Annex 1

As was indicated earlier, PE 009-15 remains the version of the PIC/S GMP Guide currently (June 2023) used by Australia’s Therapeutic Goods Administration (TGA) when inspecting manufacturers of medicines, active pharmaceutical ingredients (APIs), and sunscreens. There is currently no indication of when or whether the TGA will adopt a newer version of the PIC/S GMP Guide. Consequently, manufacturers of medicines, APIs and sunscreens for the Australian market are not formally required to comply with the requirements of PE 009-17’s revised Annex 1.

However, as the TGA has been using various versions of the PIC/S GMP Guide for over 20 years, it is essentially inevitable that in time TGA will adopt a newer version of the PIC/S GMP Guide, and from the commencement date of that adoption, manufacturers of relevant products for the Australian market will be required to comply with the requirements of that newer version’s Annex 1. Even now, PharmOut’s PIC/S GMP Training Course, and GMP eLearning for PIC/S GMP and Annex 1 can help to prepare any manufacturers who may eventually be affected by these changes, which will be in effect in other territories from 25 August 2023.

For further information about PE 009-17, any other topics that are relevant to the pharmaceutical and life sciences industries, and how PharmOut can help you, please contact us and we will be happy to help.

[1] As was adverted when the revised Annex 1 was initially published in September 2022, Annex 1 point 8.123, concerning the sterilisation of lyophilizers, does not come into force until 25 August 2024.