Author: Paul Andreianu

July 2021 – Updates from WHO

July 2021 had plenty of updates in the pharmaceutical space from the World Health Organization. As part of its weekly update for members and the general public, PQG provides a summary of these below. 

Back in 2020, the WHO published draft documents on ‘Good Manufacturing practices for medical gases’, ‘Good Manufacturing Practices for Investigational Products’ and ‘WHO Good Practices for Research and Development Facilities of Pharmaceutical Products’.

After the consolidation of comments received and a review of the feedback, revised versions of the three guidelines have now been published for the second round of public consultation. (check links for each draft guideline)

The deadline for comments is 31 August 2021. You can have your say by using the enclosed template

These along with other WHO publications can be found at the WHO Medicines website under ‘Working Documents in Public Consultation’.

 

The need for a ‘GMP for medical gases‘ comes from increased demand for medicinal gases, in particular the use of oxygen in the treatment of patients with Coronavirus disease 2019 (COVID-19). As a result of this, the World Health Organization (WHO) Health Products Policy and Standards Department (formerly Essential Medicines and Health Products) and other departments involved in the supply of oxygen and the inspection of production sites of medicinal gases, raised the urgency for the preparation of the WHO good manufacturing practices for medicinal gases guidance text.

This guideline focuses on the production, control, storage and distribution of medicinal gases, however, it does not cover the manufacturing of medicinal gases in hospitals or at home for personal use. Despite this, the principles contained in this document may be applied in those instances to ensure that oxygen generated at hospitals or at home are suitable for their intended use and meet the appropriate quality standards.

 

When it comes to the draft guideline on ‘WHO good manufacturing practices for investigational products‘, the recommendations are mainly applicable to investigational products for human use; its principles should be considered in early phase clinical manufacture.

WHO good practices for research and development facilities of pharmaceutical products‘ is specifically applicable to research and development facilities of pharmaceutical products procedures, processes and data that are intended for transfer and submission for approval in marketing authorization applications, process validation, TOT-related activities, validation, quality control laboratory activities such as stability testing and development, and validation of cleaning procedures. 

The main focus of this document is to provide for GxP in the production and control of pre-clinical and not for human use batches, manufactured in pharmaceutical formulation and development facilities, where these are directly supporting.

The principles described in this document may be applied in facilities where other products, such as biopharmaceutical products, vaccines and medical devices, are manufactured.

This guide excludes whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), medicinal gases, radiopharmaceuticals and gene therapy products.

The GxP outlined below are to be considered general guides and they may be adapted to meet individual needs. The equivalence of alternative approaches, however, should be demonstrated.

MHRA’s webinar on protecting the security of the UK supply chain – 13 August 2021 – 10 AM UK time

This MHRA webinar will raise awareness of the threat of stolen medicines being re-introduced into the regulated supply chain.

The event will be delivered by GDP Inspectors with expert knowledge of the issue and the capability to offer practical advice on steps the audience can take to protect themselves and patients from the threat and how to report suspicious activity.
This MHRA webinar is targeted at but not limited to: Wholesale dealer authorisations holders, Brokers, Responsible Persons and Quality Assurance personnel associated with wholesaling medicines.

 

To register for this free webinar use the following link.

For PQG events, add this link to your browser bookmarks or subscribe for updates. 

July 2021 – Updates from PIC/S

July has been a busy month with plenty of updates from PIC/S.

At the beginning of July 2021, PIC/S published the guidance on ‘Good Practices for Data Management and Integrity in regulated GMP/GDP environments’ (PI 041-1) following three drafts, the last being in November 2018.

It is understood that at the same time two aide memoires were also published for regulatory inspectors only – one generally on the ‘Inspection of Data Management and Integrity’ and one on the specifics for chromatographic data systems.

Later in the month (on 15 July), PIC/S published the recommendation on ‘How to Evaluate and Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management’ (PI 054-1) and ‘COVID-19 RISK ASSESSMENT FOR NATIONAL ROUTINE ON-SITE INSPECTIONS’ (PI 055-1). 

(PI 054-1) “… provides practical guidance for GMP inspectors when seeking to evaluate the effectiveness of a company’s pharmaceutical quality system (PQS) in relation to risk-based change management. It covers all relevant steps in the change management process – change proposal, change assessment, change planning and implementation, change review and effectiveness checks. It indicates within each step the aspects that render the PQS to be effective in that area.

Given this, it makes sense for you to use it to assess your own change management process before your next inspector does so!


The Purpose section provides some useful reminders of the GMP requirements for an effective PQS incorporating GMP and Quality Risk Management (QRM) generally and for a change management system in particular. It also notes that QRM is a key element of ICH Q10 and that a mature risk-based change management within an effective PQS is essential to enable greater regulatory flexibility in the reporting of post-approval changes under ICH Q12.

The checklist component of the document takes up just over three pages and follows the change management lifecycle:

• Proposals (determination of when a change is needed, including a non-limited list of common lifecycle factors that trigger change);
• Risk Assessments;
• Planning and Implementation;
• Review and Effectiveness:

o Prior to change closure;
o Prior to or after change closure, including closure of any post-implementation actions.

 

The checklist is worth working through in detail, but a few highlights include:

  • Clear documentation is required throughout.
  • The various possible impacts of changes need to be assessed.
  • The planning and implementation should include potential risks with the current state (until changes are implemented) and any risks that might be temporarily introduced during the change process.
  • Situations where proposed changes are not implemented also need to be covered.

 

In line with ICH Q9, there is allowance for the level of risk associated with a change to drive the formality and complexity of the documentation. Consideration of current process knowledge and the product/facility lifecycle is flagged. “At a minimum, changes should maintain or improve product quality and/or patient safety, and should not increase process variability.” The data needed to demonstrate effective implementation of the change should be pre-defined in change planning and confirmed on review.

Regulatory filing implications need to be addressed. 


Prepared by the PIC/S Working Group on Inspectors Safety, PI 055-1 is a risk assessment template intended to be used by inspectors, in conjunction with host sites, during the planning phase of announced GXP inspection of national sites.

It is expected that the site confirms that the necessary measures identified in the risk assessment will be implemented.

It is also noted that consideration should also be given to Covid testing of Inspectors pre and post inspection and that this may be requested by some sites. There should be two-way communication between inspectors and sites of any positive Covid test of involved personnel within the inspection window.

It is worth looking through all elements of this document and it would form a good template for any third-party audits you conduct, if you do not already have a risk assessment for these in place.


From a host site perspective, note that meeting rooms should be of an appropriate size to maintain social distancing with the number of hosts present within the same space and interacting directly with the inspector limited; if larger numbers of attendees are required then aim for participation via remote technology. Rooms should be well-ventilated, with working surfaces should be disinfected regularly.

If any of the company personnel do not co-operate with the requests of social distancing and the additional current government guidelines or become uncooperative to the NCA personnel, the inspector will leave the site immediately”, which is clearly something to be avoided!

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Manufacturing of ATMP starting materials – is GMP required?

On 23 Apr 2021, EMA published an important addition to their GMDP Q&A with the publication of ‘Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs’.

The document highlights that, whilst GMP certificates are not required for manufacturing and testing sites of starting materials for ATMPs, it is mandatory to comply with the ‘principles of GMP’.

The first Q&A covers the definition of starting materials.

Q&As 2-5 then go on to explain further what is meant by ‘principles of GMP’ for different types of ATMP manufacture. The application of a risk-based approach is expected to determine the risks presented by each material to quality, safety and function, thus determining the appropriate GMP controls and other mitigation measures.

The final two Q&As reinforce that this is an obligation of the ATMP manufacturer and confirm that a qualified person is not required for the production of starting materials.

For more details: access the GMDP Q&A entry portal or directly the document

MHRA – End of Transition Period – Week 43 Updates

The MHRA has published further guidance in relation to supplying medicines and medical devices after the end of the transition period.

On medicines we have the following updates:

On medical devices:

 

In addition to this it worth noting that DHSC has launched the new DaSH portal and published updated guidance on the reporting requirements for medicines shortages and discontinuations. The guidance is available here.

 

 

GDP Requirements and the ECA/PQG Good Distribution Practice monographs

GDP monographs will be the main topic of the webinar presented by Phil Butson (PQG) on Tuesday, 27 October.

The live webinar (GDP Requirements and the ECA/PQG Good Distribution Practice monographs) will be held on behalf of Pharmaceutical Quality Group as part of MP’s Digital Week.

During the Digital Week, Making Pharmaceuticals brings you a week of free-to-access Live Content.
The webinar is free to attend and will start at 09.30 GMT (10.30 CET | 05.30 EST).
For more details and registration click here.

Trainee QP CPD – Virtual Event 24/02/2021

The presentations from the Trainee QP, Sponsors and QP CPD Virtual Event  held on the 24th February 2021 are available in the ‘Members Only Area’. Please remember to login to access.

Data Integrity Webinar

On Tuesday 22 September 2020 PQG organised a Data Integrity Webinar with Dale Carter, Head of Quality – Evonik Corporation. 

In this presentation, Dale reviewed the recently released position paper on Data Integrity for Pharmaceutical Grade Excipients published by the International Pharmaceutical Excipients Council Federation (IPEC).

The paper was developed to supplement published Regulatory guidance defining Data Integrity requirements for drug substances and medicinal products, some of which are not easily adaptable to the manufacture of excipients.

The presentation (supporting slides available here) covered Data Integrity principles, Regulatory guidance documents and recommendations on how to apply Data Integrity to excipient manufacturing and distribution.

Week 36 – News

Just in case you missed some of this week’s news, here are the highlights:

  • MHRA published on 1 September 2020 guidance for industry and organisations to follow after the end of the transition period.

From 1 January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) will be the UK’s standalone medicines and medical devices regulator.

Transition from the EU allows the UK to offer fully independent regulatory decisions for both devices and pharmaceuticals, both nationally and in joint work with other international regulators.

Stakeholders need to get ready for new rules from 1 January 2021.

This guidance covers the following topics:

  1. Clinical trials
  2. Devices
  3. Licensing
  4. Importing and exporting (for those of you who read the previous post on PQG this is old news already)
  5. IT systems
  6. Pharmacovigilance (updated today with the new guidance ‘Guidance on QPPV including PSMFs)
  7. Paediatrics

 

  • EMA has published today the meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 31 August – 3 September 2020.

 

  • For those who chose to work late on a Friday, there is still time to provide feedback as part of the public consultation launched by EMA on joint network strategy to 2025. Use this link to access the questionnaire.

The draft strategy details how the European medicines agencies’ network can continue to enable the supply of safe and effective medicines that meet patients’ needs in the face of challenges posed by ever-accelerating developments in science, medicine, digital technologies, globalisation as well as emerging health threats, such as the COVID-19 pandemic.

It outlines six priority areas for the network:

  • the availability and accessibility of medicines;
  • data analytics, digital tools and digital transformation;
  • innovation;
  • antimicrobial resistance and other emerging health threats;
  • supply chain challenges; and
  • the sustainability of the network and operational excellence.

 

 

 

EU Exit – Acting as a RPi – Responsible Person (import) from 1 January 2021

From 1 January 2021, a wholesale dealer in Great Britain may only import Qualified Person (QP) certified medicines from the European Economic Area (EEA) if certain checks are made by the ‘Responsible Person (import) (RPi)’.

The guidance published on 1 September 2020 describes how you can apply to be a RPi, and how to verify that QP certification of a medicine has been done in the EEA.

The registration scheme for RPi candidates will be applicable from 1 January 2021 and RPi applications may be submitted through the MHRA Portal after this date.

The Responsible Person (import) (RPi) is described in regulations 45AA and 45AB of the Human Medicines Regulations 2012 (as amended) and is responsible for implementing a system to confirm that the required QP certification has taken place for products that have been imported into Great Britain (England, Wales and Scotland) from countries on an approved country for import list (initially, this will be countries in the EEA).

In scope

  • A UK or Great Britain licensed medicine for use in Great Britain
  • A UK or Great Britain licensed medicine for supply to another third country
  • A Northern Ireland or approved country licensed medicine for supply to fulfil special clinical needs
  • A Northern Ireland or approved country licensed medicine imported as an introduced medicine for supply to another third country
  • A Northern Ireland or approved country licensed medicine for use as a parallel import

Out of scope

There will products which will not require RPi oversight such as medicinal products sourced from Northern Ireland. For wholesale purposes they are out of scope of this guidance and this is permitted under the supervision of a Responsible Person (RP).

Products with a UK or Great Britain marketing authorisation that are imported into Great Britain from outside the UK  without QP certification from a country on the list will require QP certification under a UK manufacturing and import authorisation before being placed on the market.

Products without a marketing authorisation in the UK, Northern Ireland, Great Britain or a listed country are outside the scope of this guidance. Importation of such products is permitted under the supervision of a Responsible Person (RP), with notification to the MHRA of each importation that is for supply to the Great Britain market.