The Qualified Person's Notebook

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Be yourself; Everyone else is already taken.
— Oscar Wilde.

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Self Inspection

For my part, whatever anguish of spirit it may cost, I am willing to know the whole truth; to know the worst and to provide for it
Patrick Henry

Primary Guidance

This article primarily relates to legislation and approaches that are EU centric. However there are a range of GMP standards (EU, FDA, ICH etc) and each of them, requires the documentation of any deviation.

The primary EU Guidance on the principle of self-inspection is outlined in Part 1, Chapter 9 (Self Inspection) of EudraLex Volume 4 (Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use).

There is a link to the full text of this Chapter here. (EudraLex 4 – Chapter 9)

There is also reference to self-inspection in Chapter 5 (Production) here.

What is self-inspection?

All production systems are invariably human in nature and hence fallible. Self inspection is one of the mechanisms that can be used to monitor the effectiveness of a company’s own compliance with it’s marketing authorisation(s), GMP and pharmaceutical quality standards in general

It is a means of checking your own work, that can be performed with more frequency and resources (over a sustained period) than could be feasibility done by national regulators. It is also a way for a company to be frank with itself and address any areas of improvement.

Minimum requirements

Self-inspections should be conducted in an independent manner – this can be achieved by using personnel dedicated for the task or alternatively using contractors or even personnel from different parts of the company to perform the inspection itself.

As with all PQS relevant activities and detailed way by designated competent person(s) from the company. Training and competency should be recorded.

The self-inspection rota/plan should cover the following areas as a minimum.

Personnel matters (training etc)
Premises
Equipment
Documentation
Production
Quality control
Distribution of the medicinal products
Arrangements for dealing with complaints and recalls
The self inspection system / process itself

A short description of the self-inspection system with focus on criteria used for selection of the areas to be covered during planned inspections, practical arrangements and follow-up activities should also be included within the site master file.

Self Inspection Process

In general

Planning of the self inspection, in keeping with the master plan / rota
The Inspection itself
Recording and analysis of any observations and findings
Communication of the observations and findings
Proposed corrective and preventative actions if appropriate

What is the Role of a QP in self inspection?

As self inspection is a critical tool for the monitoring the effectiveness of the pharmaceutical quality system and the general state of compliance to GMP and the principles of Quality assurance within a business the QP should understand the process and be aware of its findings and be ready to propose CAPA actions based on the findings as necessary. The QP may also take part in or direct part of the self-inspection process.

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 training program.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Revision History

Version	Reason for revision / Changes made	Date
01	First Draft	15/04/2020

Introductory Principles of the Pharmaceutical Quality System

Quality is never an accident. It is always the result of intelligent effort.
John Ruskin

Primary Guidance

This article primarily relates to legislation and approaches that are EU centric. However there are a range of quality system standards (EU, FDA, ICH etc) and the level of detail worldwide devoted to the definition of an appropriate Pharmaceutical Quality System is vast. This is a summary of the EU guidance and some sections are direct copies.

The primary EU Guidance on the handling of unexpected deviations, pertaining specifically to the Qualified Person and the ability of the QP to release a batch is outlined in Part 1 (Basic Requirements for Medicinal Products), Chapter 1 – Pharmaceutical Quality System of EudraLex Volume 4 (Volume 4 of “The rules governing medicinal products in the European Union”)

There is a link to the full text of this Annex here. (EudraLex 4 – Part 1, Chapter 1). It came into operation on the 31^st January 2013.

ICH Q10 is viewed as a supplement to the primary EU guidance chapter. It can be found here but will be covered in a separate notes page.

Why have a Pharmaceutical Quality System?

The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that:

They are fit for their intended use
Comply with the requirements of the Marketing Authorisation (or Clinical Trial Authorisation)
Do not place patients at risk due to inadequate safety, quality or efficacy.

This is particularly relevant to pharmaceuticals given their risk to the patient and the potentially large impact of quality defects.

As a result, Quality Management is a wide-ranging concept and any Pharmaceutical Quality System needs to encompass all matters, which individually or collectively influence the quality of a product.

The guidance is fundamentally rooted in the understanding that correct product realisation is achieved by the structured undertaking and continuously improvement of a system that enables the consistent delivery of products with appropriate and clearly defined quality attributes.

The founding principles of a PQS

Management responsibility but supply chain wide participation. All stages are relevant

While this is the responsibility of senior management it requires the participation (and compliance) of all staff (regardless of level) in all relevant departments. This participation is also required from suppliers (upstream) and distributors (downstream).

Leadership by senior management (including QPs) and active participation and contribution to the Pharmaceutical Quality System is essential. Leadership should ensure the support and commitment of all staff at all sites. This point is repeated multiple times in the guidance, highlighting it’s significance.

The system must incorporate GMP and Quality Risk Management.

GMP, QC and QRM are all components of a wider PQS. The basic concepts of Quality Management, Good Manufacturing Practice and Quality Risk Management are heavily inter-related. They have a fundamental importance to the production and control of medicinal products. Product and process knowledge is managed throughout all lifecycle stages before GMP, during GMP and after GMP relevant activities.

The system should be traceable and in control.

The system should be fully documented with its effectiveness subject to routine monitoring. A Quality Manual (company specific or suite specific) or equivalent documentation should be established and should contain a description of the quality management system including management responsibilities. While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated/audited/reviewed at the site level.

There must be periodic management review of the Pharmaceutical Quality System to identify opportunities for continual improvement of products, processes and the PQS itself. Any system can be measured and improved.

There must be a process for self-inspection and/or quality self-audit, which regularly appraises the effectiveness and suitability of the Pharmaceutical Quality System.

The system should be adequately resourced.

Personnel should be competent with adequate training. There should be suitable and sufficient premises, equipment and facilities. The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one.

Summary of Additional PQS Expectations.

In addition to the foundational principles articulated above there are a set of more specific exceptions outline in the guidance. These are summarised below. Most are duplicative of language used in GMP specific guidance. Not all have been reproduced here as I have incorporated them into the section above.

Medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice (GMP ready, GMP “Built in”)
Production and control operations are clearly specified (Documentation)
Arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is from the approved supply chain; (Supplier audits, material traceability and control)
Processes are in place to assure the management of outsourced activities. (Audits, oversight, integration with own PQS)
A state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality. (“Traditional” Process control approaches, QbD)
The results of product and processes monitoring are taken into account in batch release, in the investigation of deviations, and, with a view to taking preventive action to avoid potential deviations occurring in the future. (Trending, Proactive CAPAs)
All necessary controls on intermediate products, and any other in-process controls and validations are carried out; (Calibration, validation, process monitoring)
Continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge. (You cannot stand still)
Arrangements are in place for the prospective evaluation of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required (Change control)
After implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product quality (Effectiveness checks, Periodic reviews, Product quality reviews)
Satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life (Temperature monitoring, stability programs)

There is also language related to the handling of deviations within this guidance. It has been included here.

Primary Role of a QP?

In addition to supporting or carrying out the responsibilities expected of management the QP has a specific role within the PQS.

Medicinal products should not be sold or supplied before a Qualified Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products (generally summarised as GMP).

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 training program.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Revision History

Version	Reason for revision / Changes made	Date
01	First Draft	13/04/2020

Introduction to the handling of unexpected deviations.

Theory is knowledge that doesn’t work. Practice is when everything works and you don’t know why
Hermann Hesse

Deviations should really be the opposite of this definition of practice. If it didn’t work, you should know and know why.

Primary Guidance

The primary EU Guidance on the handling of unexpected deviations, pertaining specifically to the Qualified Person and the ability of the QP to release a batch is outlined in Section 3, Annex 16 (Certification by a Qualified Person and Batch Release) of EudraLex Volume 4 (Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use).

There is a link to the full text of this Annex here. (EudraLex 4 – Annex 16)

What is a deviation?

Deviations (also sometimes referred to as Unplanned Deviations – however this is being supplanted by Temporary Change Controls in some regulators preferred terminology) are a state of non-compliance from implemented procedures, marketing authorisations or GMP relevant systems that might impact the manufacturing, packaging, testing, distribution or storage of drug product.

The management of deviations is not just a GMP concept, it could be used in any context relating to product quality where roles, equipment, procedures and processes will be clearly defined and stated – as in any GXP system.

There are multiple potential sources for deviations in any quality management system. These include, but are not limited to:

Unexpected variations in process/production yield
Human error
Utility malfunction or failure
Equipment malfunction of failure
Unexpected or unforeseen impacts of changes (Temporary or Permanent)

Primary Role of a QP?

Tripwire condition (my own term) – the QP can only assess a product batch, affected by a deviation, for release if the following condition is in place:

The registered specifications for active substances, excipients, packaging materials and medicinal products are met.

A QP may certify the batch or confirm compliance (with GMP, the MA etc) even if the following has taken place but is not covered within the products marketing autoriastion or genral GMP pracitice.

An unexpected deviation concerning the manufacturing process or
An unexpected deviation concerning the analytical control methods

A QP cannot assess a batch for release if a deviation has occurred that forces the product to fall outside these base criteria – i.e. if the product is out of specification.

Obviously, batches falling outside of specification may (likely will) have deviations associated with them that will still need investigation and appropriate action taken.

The basis for this assessment by a QOP is a deviation investigation. The QP must review the deviation investigation and may only release the affected batch on the conclusion that the impact is negligible. Batch may also be reworked or rejected on the conclusion of an investigation.

In a larger organisation, deviation investigations may be primarily undertaken by staff other than the QP but all deviations must be reviewed by a QP prior to a release assessment. This puts importance on the robustness of the pharmaceutical quality management system in place in terms of deviation reporting and communication.

Investigation requirements for deviations.

Deviations must be investigated for two primary reasons.

To permit assignment of a root cause and/or contributory causes. This is to permit the undertaking or corrective or preventative actions (CAPAs) to limit the impact of the deviation and to understand the extent of the deviation.

To assess the impact of the deviation. The impact of the deviation should be assessed in accordance with a quality risk management process using an appropriate approach such as described in Part III of the GMP Guide (EurdraLex Part III – Q9 – Quality Risk Management). As a minimum the impact assessment should include the following.
Evaluation of the potential impact of the deviation on quality, safety or efficacy of the batch(es) concerned
Consideration of the need to include the affected batch(es) in the ongoing stability programme.
In the case of biological medicinal products, consideration that any deviations from the approved process can have an unexpected impact on safety and efficacy.

The deviation procedure implemented within a companies quality management system should permit the detection and reporting of the deviation in real time to allow for prompt investigation. The investigation itself should be completed in a timely fashion (30 days or less is the current industry expectation) and corrective actions should be recorded and monitored for effectiveness.

Corrective actions may be immediate in nature or may require significant time and resource to resolve. Preventive actions, if required and implementable, should be taken to ensure prevent reoccurrence of the deviation. All actions should themselves be recorded and assessed in line with quality risk management principles if appropriate. These actions may require undertaking within a change control system and could involve communication with the regulatory authority including the submission of a variation to the MA for the continued manufacture of the product.

The recording, reporting and investigation of deviations is mandated and expected in GMP but the deviation procedure, if implemented properly, can be a powerful components in a continuous improvement focussed quality management system.

Additional requirements for deviation are mentioned in the wider EU guidance.

In Chapter 1 – Pharmaceutical Quality System the additional points are raised.

In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those.
Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present.

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 training program. If you find it helpful or if you want to take issue with the content please leave a comment.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Revision History

Version	Reason for revision / Changes made	Date
01	First Draft	12/04/2020
02	Addition of detail from Chapter 1 of the EU Guidance.	13/04/2020

Validation

To Validate;

verb

check or prove the validity or accuracy of

Within Good Manufacturing Practice Validation is a means of assuring the quality of a process or a product.

Companies need to demonstrate that they can make the product they have proposed to market in a consistent manner with a level of quality that is fit for purpose. They must then demonstrate their continued ability to make the same product, to the same quality standard (or higher) over the entire life-cycle of that product.

Validation is demonstrating, with documented evidence, that each step of the manufacturing process performs as expected. It requires showing that testing methods are fit for purpose.

Therefore, each critical step in the manufacturing process must be verified to perform as intended under defined conditions.

Qualified People and the Qualified Person

A key requirement of ensuring that a product is made correctly is ensuring that everyone who contributes to the production of that project is correctly trained. An example that’s easy to understand is an operative that cleans the room or location that manufacturing takes place in. That operative must know the limits of their responsibility and be competent in ensuring that their work is completed to a clearly understood standard. If the operative fails to clean the manufacturing environment a contaminant may get into the final product which may cause a batch rejection, or worse. Everyone involved, even indirectly, with GMP must take personal ownership of their standard of training and their work.

Within European Good Manufacturing Practice a special and distinct role exists, the Qualified Person (QP). The qualified person is a senior member of the quality team that is obliged by law to review the sourcing, manufacturing, testing and quality assurance of the batch of product to be released. Their approach must represent the pinnacle of GMP knowledge and outlook.

The power of using a Qualified Person is personal accountability. It ensures that the ultimate decision to release a batch of product into the market is traceable to an individual decision point. This helps ensure that organisational concerns such as profit making can be balanced better against what is best for the end user.

While a QPs role is daunting with the European GMP framework its always vital to remember that a QP will rely on the experience, training, honesty and compliance of the members of her/his company to be trained in what they do and to do the right thing.

Necessity, Born of Tragedy

Good Manufacturing Practice is a series of regulations, practices and philosophies that simultaneously constrain and enable the manufacturing of pharmaceuticals and medicines that are subject to widespread marketing.

They exist primarily to protect the public from the consequences of unconstrained or unregulated medicinal manufacturing. Many examples exist from history of tragedies, widespread and local, were unfortunate people died of suffered serious harm as a result of poor or uncontrolled manufacturing.

Good Manufacturing Practice, when implemented correctly should ensure that medicinal products are made to a standard that ensures they are safe if used correctly, represent the highest standards of product quality and do exactly what they say on the label. Every. Single. Time

Introduce Yourself (Example Post)

This is an example post, originally published as part of Blogging University. Enroll in one of our ten programs, and start your blog right.

You’re going to publish a post today. Don’t worry about how your blog looks. Don’t worry if you haven’t given it a name yet, or you’re feeling overwhelmed. Just click the “New Post” button, and tell us why you’re here.

Why do this?

Because it gives new readers context. What are you about? Why should they read your blog?
Because it will help you focus you own ideas about your blog and what you’d like to do with it.

The post can be short or long, a personal intro to your life or a bloggy mission statement, a manifesto for the future or a simple outline of your the types of things you hope to publish.

To help you get started, here are a few questions:

Why are you blogging publicly, rather than keeping a personal journal?
What topics do you think you’ll write about?
Who would you love to connect with via your blog?
If you blog successfully throughout the next year, what would you hope to have accomplished?

You’re not locked into any of this; one of the wonderful things about blogs is how they constantly evolve as we learn, grow, and interact with one another — but it’s good to know where and why you started, and articulating your goals may just give you a few other post ideas.

Can’t think how to get started? Just write the first thing that pops into your head. Anne Lamott, author of a book on writing we love, says that you need to give yourself permission to write a “crappy first draft”. Anne makes a great point — just start writing, and worry about editing it later.

When you’re ready to publish, give your post three to five tags that describe your blog’s focus — writing, photography, fiction, parenting, food, cars, movies, sports, whatever. These tags will help others who care about your topics find you in the Reader. Make sure one of the tags is “zerotohero,” so other new bloggers can find you, too.