GMP Compliance Adviser Update No. 5/2020

With this GMP Compliance Adviser UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

GMP in Practice

Chapter 1

Quality Management Systems

1.O Regulatory compliance – how to optimize


Chapter 21

Inspections and drug safety

21.C Frequent deficiencies in GMP inspections,
their recurring pitfalls and how to avoid them

21.E Self-inspection




Chapter 21

Inspections and drug safety

Analysis of FDA FY2019 Drug GMP Warning Letters  

GMP Regulations

Chapter C 

EU Directives and Guidelines

C.11 Guideline on the quality of water for
pharmaceutical use

C.11.1 Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies


GMP in Practice

Chapter 19 Quality Management Systems

Chapter 1.O Regulatory compliance - how to optimize

As outlined in ICH Q10 Pharmaceutical Quality System, there is an expectation that there is an integrated Quality organization that partners with Operations and Research and Development to deliver high quality products to patients, and that allows Senior Management to be aware of and involved in mitigating non-compliances.
A firm with a proactive compliance program has developed a process, involving Operations, Quality, R&D and Compliance, to self-identify potential issues before there are any negative effects, assess the risk associated with the potential issues and prioritize remediation of the issues so that the most severe are corrected first. Finally, Senior Management is aware of any significant issues at the site, can assess and verify lower level decision making and ensure the correct prioritization and resources are available for remediation efforts.
By implementing a program as described in this chapter, you will be well on your way to establishing a robust, compliant operation that will continually improve by reducing errors and variability. (Mark Tucker, PhD)

Chapter 21 Inspections and drug safety

21.C Frequent deficiencies in GMP inspections, their recurring pitfalls and how to avoid them

In some areas, GMP inspections reveal "recurrently similar" GMP deficiencies, such as

  • insufficiently detailed root cause analysis when dealing with deviations,
  • lack of consideration of the actual data paths and frequent media changes or transfer steps in hybrid systems or at interfaces of different systems in the course of validation of computerized systems, or
  • incomprehensible processing of complaints, which are production-related, but whose batch documentation is "inconspicuous".

If, for example, in the case of deviations, the root cause analysis is not carried out in sufficient detail, the "most likely" cause often cannot be identified. This means that implemented measures have no effect. The deviation is repeated. And the GMP deficiency is preprogrammed.
In this chapter the underlying problems are described using such examples. Backgrounds are discussed and common pitfalls are pointed out. You will then receive concrete suggestions for avoiding the single deficiencies.
The lack of root cause analysis could be avoided, for example, by "thinking it through". Put a first "snapshot" on the most likely cause through its paces. How did this cause come about? Why? Ask deeper.
But sometimes questions alone do not get you anywhere. In the event of complaints, it is often asked about anomalies in the batch documentation. However, the answer is often "inconspicuous". Even if the sub-sequent examination of the complaint pattern indicates a problem during production, e.g. a machine stop. The answer "batch documentation inconspicuous" apparently does not fully reflect the manufacturing process for this batch. How can this discrepancy be explained and how can it be resolved?
Stay curious – about this chapter and about your daily work. Detach yourself from the routine every now and then and ask yourself: Why? (Lea Joos)

21.E Self-inspections

Self-inspections are not only used to monitor quality levels, but for continuous improvement also because they can also be used to identify potential risks and areas of improvement. This requires that all parties involved display a high level of awareness and communicate openly.
In the course of self-inspections, all areas that have a potential influence on product quality are checked. The inspection fields can be defined as department-oriented, process-oriented or system-oriented.
The definition of inspection frequencies is at the discretion of the pharmaceutical company. It can be risk-based or for-cause, or it can provide for fixed intervals.
Inspectors for self-inspections require not only professional expertise but also good communication and organisational skills.
Self-inspections have to be planned, carried out and documented in accordance with written procedures. Usually, after a review of the documents, an on-site inspection is carried out. All observations are documented. The final report contains an assessment of the compliance with GMP and company-specific requirements.
If deficiencies are detected, they should be evaluated and eliminated using a standardised process. It makes sense to use a classification scheme that is similar to that used during official inspections and audits to facilitate comparability.
If self-inspections are planned meticulously and carried out using checklists or aide-mémoires, they are a meaningful and effective way of checking GMP status and ensuring continuous quality improvement.
Like all QA systems, the self-inspection system must be regularly checked for effectiveness. The result is part of the management review.

GMP Regulations

Chapter C EU Directives and Guidelines

C.11 Guideline on the quality of water for pharmaceutical use

On 20 July 2020, EMA published the final 10-page Guideline on the quality of water for pharmaceutical use.
Please note: The date of entry into force will be 1 February 2021.

From that date on the guideline will replace

  • the Note for guidance on quality of water for pharmaceutical use from 1 May 2002
  • the CPMP Position Statement on the quality of water used in the production of vaccines for parenteral use from 20 October 2003.

It takes into account the following interim changes to the European Pharmacopoeia:

  • the revised monograph on Water for Injection (0169), which offers the possibility of using processes other than distillation for WFI (Water for Injection), e. g. reverse osmosis
  • new monograph on water for the production of extracts (2249) and
  • the suppression of the monograph for HPW, highly purified water (1927)

It also reflects the expectations for the minimum acceptable water quality in the manufacture of active ingredients and medicinal products for human and veterinary use.
The document also applies to ATMPs (Advanced Therapy Medicinal Products) and can in general also be applied to investigational medicinal products (IMPs).

C.11.1 Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies

The new guideline on the quality of water compliments this Q&A paper. Both documents should be read together. The Q&A has already been published following the revision of the WFI monograph (0169) in 2017.

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