Annex 1 – Revolution in GMP heaven?

The new Annex 1

a document that is awaited with more excitement than ever before in the history of GMP regulations. One reason for this is that Annex 1 has now been available as a draft for more than 4 years and its publication has been repeatedly delayed for various reasons. According to current information, the publication is now scheduled for September 2022.

What is new and therefore very special?

On the one hand, the (recommended) scope of Annex 1 has been significantly expanded. In future, the focus will no longer be solely on the manufacture of sterile medicinal products, but it is recommended that “principles can also be used to support the manufacture of other products that are not intended to be sterile, such as certain liquids, creams, ointments and biological intermediates with low biological load”. It can therefore be assumed that the requirements, e.g. for the definitions of cleanroom zoning and the associated qualification and implementation of monitoring, will then also be applied to other production facilities that were not previously included in the Annex 1 control loop.

Monitoring of processes

The topic of monitoring processes, including the requirements for the expertise of all those involved in the value creation process, is then very much in focus and clear expectations are defined. For example, the specification of the bacterial load in the A zone changes from previously < 1 CFU/m³ air volume in the monitoring of room conditions to 0 CFU/m³ (“no growth”) with the expectation that every occurrence of a germ is immediately transferred to an investigation (deviation), with the requirement that the “real cause” is also determined. Annex 1 then formulates the requirement that the process control in the manufacture of sterile medicinal products is closely monitored, e.g. with the requirement of QA monitoring through windows in the cleanroom that allow a complete view of the processes, or alternatively by means of recording cameras.

The central theme in Annex 1

however, is the requirement to implement a so-called contamination control strategy (CCS) in the company, which, on the basis of a detailed risk analysis, determines the corresponding assessments of possible influencing factors for the occurrence of particulate or microbial contamination and defines the strategic measures for defense / monitoring. In the current reading of the new Annex1 , this is to be interpreted as meaning that, in addition to the SMF and VMP, a further strategy document should be created and maintained at a high level in the company’s organizational structure on the basis of a well-implemented risk management system.

Overall, Annex 1 has become much more technical. This is the first time that the media systems have been recorded in great detail and clear requirements for the design / definition of acceptance criteria have been formulated and specified.

APS (Aseptic Process Simulation)

A large part of the new Annex 1 is taken up by the actual production, including the chapter of the APS (Aseptic Process Simulation) formerly known as MediaFill. There are not necessarily any revolutionary changes, but there is a significantly greater specification of current practice combined with the requirements for the qualification of those involved and the targeted use of the risk management system.

Conclusion

Very exciting, very ambitious. With publication, it will be a major task in the company to evaluate the many clarifications / new requirements and changes, and to derive and implement the right conclusions with regard to implementation.

More information

Please contact us for further training and consulting services relating to Annex 1 via e-mail info@expertsinstitut.de

Target group

The online seminar is no longer only aimed at employees working with sterile medicinal products, but is open to the entire spectrum, i.e. everyone involved in the implementation / execution of Annex 1 in the company. Departments such as production, quality, QA / QC, as well as engineering, plant manufacturers and also inspectors benefit from the knowledge imparted in this seminar. Contact: info@expertsinstitut.de

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EudraLex Vol. 4 Part IV: One for all?

Biotechnologically produced drugs are booming

Advanced therapy medicinal products (ATMPs) are at the forefront of regulatory developments, including good manufacturing practice requirements. A still very young ATMP GMP guide is going down paths that have not yet existed in the GMP universe.

GMP regulations – EudraLex

Firstly, the 90-page guide is largely independent of other GMP regulations. This is very surprising, as the annexes of the GMP Guide in particular have almost always been applied to all other pharmaceutical situations. However, there are hardly any references to the classic annexes in the ATMP guidelines.

Regulations Compliance

ATMP Guide

Secondly, the new ATMP Guide promotes a more risk-based approach in the pharmaceutical quality system. This may not sound new in principle, but in terms of conventional GMP requirements, it certainly is. If the Guide is interpreted literally, there are some degrees of freedom that historically did not exist for the manufacture of medicinal products or that were often not granted in practice despite ICHQ9 / GMP Guideline Part 3 – depending on the supervisory authority.

GMP special regulations

Thirdly, there are some special GMP regulations for ATMPs, such as decentralized release or concessions to process validation requirements. It is worth studying the text carefully, as much of it sounds similar to the familiar GMP regulations, but on closer inspection the details are different. And it adds up(!).

Finally, the ATMPs GMP guideline also sets out its own rules for investigational medicinal products. No wonder, because the IMP GMP Guide, which is also very new and is currently placed under EUDRALEX Volume 4 Annex 13, does not apply to I-ATMPs. In clinical development, this also means that it pays to take a closer look.

Conclusion

The latest ATMP guideline is not only a helpful tool for clarifying the regulatory expectations of GMP. But it also takes an important step away from a less rigid application of fixed and sometimes excessive specification lists (GMP overkill), towards an adapted GMP approach – namely quality assurance based on technical knowledge and compliance awareness.

It remains to be seen whether the European way of thinking will prove to be compatible with the requirements of other countries, or whether this fundamentally sensible EU approach will simply have to serve an additional compliance world that will not exist anywhere else in the world.

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The new ANNEX 1 02/2020

ESSAY No. 1 – Acceptance criteria for germ count monitoring in cleanrooms

One of the significant revisions in the draft of the new Annex 1 is the change in the limitation of the bacterial count in cleanroom class “A”. Whereas the previous requirement was that a maximum value of “< 1” was permitted in the core zone of aseptic production, the limit is now set to “no growth”, i.e. “0” CFU/sampling.

Sampling point

This will be a challenge in the future because, in contrast to the new requirement, the current value is an average value per sampling point (air bacteria count, sedimentation plate, contact plate)1) , which means that the number of 1 bacteria can theoretically be exceeded in a sample. According to general GMP understanding, the new requirement implies that the occurrence of a germ immediately leads to an investigation as part of the company’s own deviation management, whereby the cause of the origin of the germ should be found with the greatest possible probability.

Requirement in the new Annex 1

If the requirement in the new Annex 1 is included in the ongoing discussion that in future it should be possible to fully monitor the cleanroom from outside, i.e. outside the A/B zone (suitable windows or camera systems are specifically recommended), this presents a new challenge. In FDA inspections, for example, it is already expected that monitoring activities (quality oversight) will be specifically incorporated into the evaluation of microbial findings in order to establish the greatest possible correlation between the sample train carried out and the event that took place.

For the pharmaceutical manufacturer

In the interpretation of the new Annex 1, this means for the pharmaceutical manufacturer: establishment of documented monitoring of the cleanroom with chronological allocation of sampling/monitoring and events that actually took place in the cleanroom. An exciting task!

Source: 1) ZLG Aide memoire “Monitoring of sterile manufacturers”

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GMP reagent management: Many unspoken rules?

So inconspicuous and yet so important, especially from today’s perspective: Section 6.19 of Chapter 6 of the EU GMP guidelines once again significantly increased the effort required to carry out analytical tests:

6.19 Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.

Miniature manufacturing instructions

If strictly interpreted, this means that a miniature manufacturing instruction and therefore also a specification should be created for each affected article – and of course all of this should be integrated into the usual document control system. No, this has not yet been an explicit requirement to this extent, even if it was tacitly expected in some inspections.

But that’s not all: in order to determine whether and how often, for example, a reagent itself must be tested analytically, stability data must now be used(!) – in a strictly literal interpretation.

Pharmacopoeia descriptions

There are plenty of unanswered questions: Can pharmacopoeia descriptions (if available) replace written manufacturing instructions for reagents? Do expiry dates or re-test data from reagent suppliers also count as stability data in the broadest sense (and this is still not clear)? If I change the manufacturer of an initial reagent, do I have to document everything via a change control procedure, i.e. is this a ‘significant’ change?

No footnotes, no Q&A document from the EMA – until now. However, the consequence of non-compliance with section 6.19 is clear: in extreme cases, analysis results may be called into question and retesting of already marketed products may be necessary as a follow-up measure. Where results were included in the assessment of critical incidents (e.g. OOS events), a reassessment may also be appropriate.

Our recommendation: The legislator has obviously deliberately made long-standing unspoken requirements much clearer. If your lab has any gaps here, don’t put it off, but make an action plan now to fix it! Definitely better than only reacting when the child has fallen into the (GMP inspection) well…

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The GMP Management Review

The GMP Management Review: A highly underestimated instrument of quality assurance

The GMP Management Review: A highly underestimated instrument of quality assurance

The management review is not a new instrument in the GMP quality system; it is also a topic within the latest EU GDP Guidance. Nevertheless: in reality, many GMP companies still do not really know how to deal with this topic – the implementation of the management review is completely lacking in some places. Where does that come from…?

Quality system ICHQ10

It is often not clear to the management and senior management of a GMP company how this requirement for a management review fits into the existing quality system, let alone what the background and purpose of the requirement is. The answer is described in the Guidance on the Pharmaceutical Quality System ICHQ10 – as part of the EU GMP Guidance (Part III Q10), every company should be familiar with this document for its own benefit.

The lack of establishment of the management review

However, the lack of establishment of the management review is not just another item on the list of inspection deficiencies – unfortunately, it is much more serious: for many companies, the management review is part of an actual reorganization of the quality system – in accordance with ICHQ10.

GMP guidelines

Gone are the days when anyone could set up a quality system as they saw fit based on the chapters of the GMP guidelines – a collection of SOPs and processes from the guidelines that were linked together as best they could to form a quality system. Anyone who has not yet realized that ICHQ10 must be the leading principle – the big bracket around the pharmaceutical quality system of a GMP company – has some catching up to do.

ICHQ10

Does this mean having to completely rebuild a quality system? In most cases, adaptation to ICHQ10 should be feasible with manageable effort. However, anyone who has not taken ‘quality management’ in the GMP guidelines seriously for many years – i.e. has seen it more as a formality than an effective management tool – will now have to invest in order not to completely miss the boat when it comes to the GMP compliance required today. And that’s right: this applies not only to the developers of new drugs and their legacy products, but also to manufacturers of generics.

Conclusion

The ray of hope: The management review according to ICHQ10 is not just a manageable hurdle. In particular, the mandatory involvement of senior management means that this is the best opportunity to date to overcome the long-standing and well-known shortcomings of the in-house quality system.

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Media systems – new chapter in Annex 1

Media systems in Annex 1: Vacuum and cooling systems

One of the new chapters in Annex 1 deals with media systems. In addition to requirements for the design and operation of water systems, vacuum and cooling systems are also listed for the first time. Among other things, the new Annex 1 covers the requirement:

“6.23 There should be periodic cleaning/disinfection for both vacuum and cooling systems.”

Condensation phenomena

My comment: This requirement can be misunderstood. This does not mean, for example, that the piping system of the coolant should be cleaned / disinfected (as the first requests for comments have already been received by gmp-experts), which will be difficult as a purely technical system. Rather, this refers to the areas of installations where condensation can lead to localized and permanent moisture formation and thus the risk of germ formation and even biofilm formation.

Regular checks

What should you do? Regular monitoring means integrating these points into routine hygiene monitoring and regularly cleaning and disinfecting the affected areas, e.g. in the refrigerator, but also in the cooling register of a ventilation system. For the latter, the application of VDI 6022 Sheet 3, for example, would be highly recommended. A very good basis for a suitable hygiene plan is provided here in the form of a directly implementable checklist.

Cleaning / disinfection of vacuum systems

The cleaning / disinfection of vacuum systems primarily refers to all systems that are used to remove loads (heat, vapors, moisture, particles) from the environment of the product / process (generally referred to as source exhaust air systems). These can be classic extraction systems on workbenches, vacuum cleaners or permanently connected central extraction systems on process plants (e.g. vapor extraction systems on washing machines).

Pipes / fittings and filters

In any case, cleaning / disinfection in relation to the corresponding clean room zone in which the system is located includes the removal of all contaminants from pipes / fittings and filters that could return to the process / product in the opposite direction to the suction direction during operation.

Requirement from Annex 1

Conclusion of this new requirement from Annex 1, which deals with media systems: A corresponding maintenance / cleaning plan and integration into routine monitoring as a GMP routine is the necessary basis for this and should be included in the company’s hygiene system as an important part of the Contamination Control Strategy (CCS).

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Chapter 6 in the new Annex 1: Supply and media systems

News from Annex 1:

A very interesting statement comes from Annex 1, which in the opinion of gmp-experts should be treated with caution and above all with good GMP expertise:

WFI systems

The new Annex 1 is listed under Chapter 6 – Supply and media systems in subsection 6.15:

“WFI systems should include the use of continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these can give a better indication of biofilm formation that individual samples would not always detect. The placement of sensors should be based on qualification.” (Translation from English by gmp-experts)

Distribution system

To this end:

If a TOC measuring device determines that there is a biofilm in the distribution system, all other GMP systems from the planning, installation, qualification, operating mode and monitoring of ultrapure water systems carried out under the keyword “hygienic design” have categorically failed.

TOC meter

If there is an increase in the values on the TOC device, there must be an extremely high (continuous) bacterial load in the distribution system. In order to detect a ppb of TOC content in the water, a much higher bacterial load in the water is required than the specification requirements according to Pharm.-Eur. allow. If, on the other hand, a single biofilm floc were to find its way into the minimum volume flow of a TOC measurement, this would have to be described as an extremely high random factor.

Biofilms are generally very stationary systems that are more likely to be found in the regions of a water system where things tend to be calm, i.e. without much turbulence. This is therefore more likely to be found in the area of valves (if they are not used / decontaminated for a long time), in narrow gaps where the capillary force with high suction pressure (approx. 0.3 bar at 10µm gap size) allows water to enter, for example, tri-clamp connections or the clamping area of membranes on valves, where a biofilm can form very locally and become firmly established in the long term after the appearance of a germ.

GMP conformity for ultrapure water systems

In principle, GMP conformity for ultrapure water systems is subject to the conditions of a suitable design (hygienic design) and operating mode (production / decontamination) in conjunction with comprehensive, risk-based monitoring. This is the only way to ensure that biofilms can be avoided, eliminated and, above all, detected.

The TOC measuring device detects the total content of organic carbons, which can have many causes, e.g. the presence ofCO2 as a non-condensable gas. Therefore indispensable measuring principle, but not suitable for the intention of Annex 1.

News from Annex 1 – Conclusion

For further discussion of the topic, please refer to the detailed explanations EMA/INS/GMP/443117/2017GMP/GDP Inspectors Working Group: Questionsandanswersonproductionofwaterforinjectionbynon-distillationmethods-reverseosmosisandbiofilmsandcontrolstrategies

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Process validation

Process stability – process capability – controlled state –
Important terms that should not be missing in any current process validation!

Guidelines for process validation

In the current guidelines on process validation (FDA Guidance, Annex 15, Aide memoire 07122901) as well as in more and more inspection reports, there is a requirement for proof of process stability, process capability and the continuation of the controlled state. What is meant by this?

A stable process is a process that predictably delivers products of comparable quality batch after batch. This state can also be referred to as a “controlled process” or a “process under (statistical) control”.

However, process stability does not automatically mean that the process also delivers a product that conforms to specifications. A stable process can also predictably deliver products that are not of the desired quality.

Process stability

Fig. 2: Stable process that violates the specification limits

Therefore, in addition to the term process stability, the guidelines also include the requirement for appropriate process capability. The calculation of the process capability in the form of the process capability index (Ppk or Cpk) sets the scatter of the results and the position of the mean value in relation to the specification limits. High process capability means that the results are so far away from the specification limits that it is very unlikely that OOS results will occur in the batch.

If a process is stable and has good process capability, a product is manufactured that is firstly comparable with the previously produced batches (process stability) and secondly lies safely within the specification limits (process capability).

Process capability

However, the terms process stability and process capability always refer only to a single product characteristic, e.g. the content of the medicinal product, and not, as the terms imply, to the entire process. It is therefore quite possible that a process delivers tablets with reproducible, specification-compliant content, but that these show completely different active ingredient releases from batch to batch.

Product features

Accordingly, it is essential to first identify all critical product features that need to be assessed as part of process validation in a risk-based manner and then, in a second step, to check whether the process is stable and capable with regard to all critical product features.

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Proof of process stability

The EU and FDA guidelines on process validation require that the process stability of manufacturing processes must be proven. How can this be achieved?

Control charts for evaluating process stability

A simple and effective way to analyze your data with regard to process stability is to display the results to be evaluated in control charts.

In contrast to the Excel charts usually used in process validations, the control chart does not contain any acceptance criteria, but statistical key figures that allow the current production to be compared with previous productions. For example, the plotted mean value of previous results can be used to identify mean value shifts in current production (see Fig. 1), while the display of warning and intervention limits allows the scattering of results to be evaluated (Fig. 2).

Calculation and practical significance of the intervention limits

The warning and intervention limits in control charts are calculated from the mean value and the standard deviation of the sample, which should comprise at least 30 data points.

This is based on the assumption that, in the case of a nominal distribution, 95 % of the values lie within the range of mean ± 2σσ and 99.7 % of all values lie within the range of mean ± 3σσ (see Fig. 3).

What does that mean?

If 100 values are entered in the control chart, no values outside the intervention limits may occur with an unchanged stable process and only 5 values may be in the range between the warning limit and the intervention limit.

If 1000 values are entered in the control chart, only 3 values will be outside the intervention limits if the process stability remains unchanged.

What else is important:

Setting intervention limits based on the results of only a few batches, e.g. three process validation batches, carries the risk of underestimating the “normal” inter-batch variability, i.e. the differences between the individual batches, so that the calculated intervention limits may not be sufficient. are too narrow. It therefore makes sense in this case to clearly state that the limits determined are provisional limits that will be adjusted in the further course of batch production as soon as further findings on inter-batch variability have been obtained.

By the way: By using control charts, you are using a statistical tool and thus already fulfilling the requirement for statistical analyses of your data!

If you have fewer than 30 data points from the production of previous batches, it makes more sense to carry out a purely visual evaluation of process stability based on diagrams without intervention limits, but with the reported acceptance criteria.

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Sensible limit values for process capability

The calculation of the process capability in the form of the process capability index (Ppk or Cpk) sets the scatter of the individual results and the position of the mean value in relation to the specification limits. The higher the process capability index, the further away the individual results are from the specification limits.

Calculation of the process capability index:

The following parameters are included in the calculation of the process capability index:

  • Mean value (μ)
  • Standard deviation of the mean value (σ)
  • Upper and lower specification limit (OSG and USG)

The first step is to calculate the process capability indices “Cpo” and “Cpu” for the upper and lower specification limits:

Cpo = (OSG – μ)/(3σ) OSG = upper specification limit

Cpu = (μ – USG)/(3σ) USG = lower specification limit

Cpk = min(Cpo, Cpu)

In a second step, the lower value (Cpk = smallest process capability value) of the two values is selected:

The calculation of meaningful Cpk values is only possible from 25 – 30 individual values.

Sample calculation:

Investigated quality characteristic: content of a medicinal product

Specification limits: 95 – 105 mg

Average value: 98 mg

Standard deviation: 0.5 mg

Cpo = (105 mg – 98 mg)/(3×0.5 mg) = 4.7

Cpu = (98 mg – 95 mg)/( 3×0.5 mg) = 2.0

Cpk = min(Cpo, Cpu) = 2.0

But what do the Cpk values obtained mean?

Cpk = 1.00

If 1 million units are checked, 2699 faulty units would be found. The distance of the mean value to the next specification limit corresponds to 3 times the standard deviation (3σ) of the values.

Cpk = 1.33

If 1 million units are checked, 66 faulty units would be found. The distance of the mean value to the next specification limit corresponds to 4 times the standard deviation (4σ) of the values.

Cpk = 1.67

If 1 million units are checked, no faulty units would be found. The distance of the mean value to the next specification limit corresponds to 5 times the standard deviation (5σ) of the values.

Cpk = 2.00

If 1 million units are checked, no faulty units would be found. The distance of the mean value to the next specification limit corresponds to 6 times the standard deviation (6σ) of the values.

The limit values selected for the CpK value should be determined on a risk basis. This means that the more critical a quality characteristic is, the higher the acceptance criterion for the CpK value should be.

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