Comparative Analysis: PQS Requirements for API, Medicinal Products, and ATMPs
The pharmaceutical guidelines around the scope and application are full of areas that could be viewed as redundant or duplicative, whilst also being frustratingly nuanced and distinct.
I believe this is mostly driven by the nature of guidance development - where the core guidance has sat with relatively small tweaks over time, in contrast to larger chunks of guidance that have been “bolted on”. At the same time some aspects of the guidance acknowledge that quality system requirements are less strict for more upstream activities such as AS manufacture.
The end result is two or three “versions” of what's required in a PQS depending on the activity under consideration and it can be challenging to keep everything straight.
Bearing in mind that you may be asked to compare and contrast these three page turning bestsellers….
Let's delve deeper into a comparison of the pharmaceutical quality system requirements for medicinal products (EudraLex Vol. 4 Chapter 1) API production (EudraLex Vol. 4 Part II - Basic Requirements for Active Substances used as Starting Materials) and ATMP production (EudraLex Vol. 4 Part IV - GMP requirements for Advanced Therapy Medicinal Products).
1. Management's Commitment to Quality:
All three guidance documents focus on senior management's responsibility for quality, ensuring a quality system is in place and maintained. Part IV (ATMPs) emphasises an additional focus on ensuring that specific challenges, such as the use of living organisms and the inherent variability in starting materials, are addressed.
2. The basics:
All three guidance documents focus on similar core building blocks of quality such as:
Quality is designed in
Personnel are appropriately qualified and trained
Premises and space are adequate to the task
Access to suitable equipment and services
Production and testing makes use of correct materials, containers and labels
Operations follow approved procedures and instructions, in accordance with the Pharmaceutical Quality System
Suitable storage and transport arrangements exist for products, intermediates and materials
Product and process knowledge is managed
3. Internal Audits (Self Inspection):
In all documents a requirement is outlined for a self-inspection process and/or quality audit, which regularly appraises the effectiveness and applicability of the Pharmaceutical Quality System. Part IV is slightly odd in its language that it mentions that “Results of parameters identified as a quality attribute or as critical should be trended and checked to make sure that they are consistent with each other.” which is arguably a requirement that should better sit in the QC/production guidance.
4. Role of the QP:
While the role of the QP is more fully established in Annex 16 as opposed to Chapter 1 it does specify the need for a QP certification prior to batch release for sale. Part IV (ATMPs) emphasises an focus on additional QP training and experience related to the more challenging technical aspects that ATMPs face, such as the use of living organisms and the inherent challenges in their control and characterisation. No requirement for a QP exists within AS GMP (Part II) but release of finished AS is under control of the quality unit.
Part IV does have some significant differences from “standard” Annex 16 which I hope to cover in more detail an upcoming post.
5. Product Quality Reviews:
Both Chapter 1 and Part II mandate the requirement for a PQR for both finished products and ASs respectively.
AS PQRs do not mandate the same level of detail - namely a specific requirement doesn’t exist for a review starting materials or for the qualification status of equipment and utilities. Reflecting ASs differing status w.r.t licencing and registrations less detail is required regarding the status of marketing authorisations or licensing variations.
Part IV does specify the need for annual quality reviews (the term PQR is absent) but is much less specific in what needs included. There is a general expectation that the depth of the PQR scales with the scale of how much has been made each year - little product - short PQR, lots of batches - big PQR. Same in general concept to Chapter 1 but worded differently - just to keep you on your toes.
6. Complaints, Deviations, and Recalls:
All three guidance documents focus on management's responsibility for quality, ensuring a quality system is in place and maintained. Part IV (ATMPs) emphasises an additional focus on ensuring that specific challenges, such as the use of living organisms and the inherent variability in starting materials, are addressed.
8. Risk based approach vs Quality risk management:
The overall principles of QRM are stated identically in Chapter 1 and Part II in what is a truncated reading of the principles that kick off ICH Q9, Part IV (ATMPs) introduces language related to the adoption of a “risk based approach” which isn’t mentioned in the other (older) guides.
Both sets of language emphasise the same principles - primarily the allocation of resources and attention efficiently, focusing on high-priority risks and be based on current scientific knowledge.
However a key difference is that the RBA includes language related to flexibility and provides examples where a manufacturer may depart from specific guidance if they believe they have an approach that provides an acceptable level of risk.
This may seem counterintuitive to the language that states that a “risk-based approach can facilitate compliance but does not obviate the manufacturer's obligation to comply with relevant regulatory requirements” but a key clarification is that exemptions from specific guidance should be (in particular for approved ATMPs) agreed with the competent authorities and generally be described within the marketing authorisation. This permits the language around exemptions to align with a core piece of more “traditional” GMP where specific examples of potential GMP exemption have been previously permitted for certain products or processes where pre-agreed with the competent authority - see Annex 4 section 10 for an example.
More united than divided:
Even if the style and structure of each document is somewhat maddingly distinct, all three guidance documents focus on the effective use a PQS to support and ensure quality product realisation. It’s critical to bear in mind that the PQS is first and foremost an enabling toolset as opposed to a restrictive requirement.
Part IV (ATMPs) emphasises more explicitly the additional role of the PQS to ensure that data obtained from the early phases of a clinical trial can be used in subsequent phases of development i.e. a primary driver is knowledge management and the preservation of the critical information that permits the product to work.
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Disclaimer
This document is not a legal document not should it be interpreted in any fashion as a guide. This is a set of notes compiled as part of a personal CPD program. It is not complete or authoritative. I hope it gives you some value.
This is a personal effort and is not affiliated with my current role or employer.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. If you use it to train someone else, fantastic, but give the QP Notebook a plug. Thanks