LOGFILE Feature 37/2019 – EDQM inspections and trends of deficiencies relating to API facilities

 08.10.2019

EDQM inspections and trends of deficiencies relating to API facilities

10 minutes reading time

by Tim Sandle

In recent years, there has been an increase in international drug inspections to assure that good manufacturing practice (GMP) is being appropriately applied no matter where a bulk pharmaceutical chemical or active pharmaceutical ingredient (API) is made. With the regulation and inspection of API manufacturers falling under agencies operating in the European Economic Area, there has been little (until now) trend data relating to facility inspections.

As part of transparency in relation to the European Directorate for the Quality of Medicines (EDQM) Inspection Programme, the European Union directorate has issued an overview of common trends and findings titled “EDQM Inspections and Trends of Deficiencies Overview 2006 to 2018”[1]. This document was issued in May 2019. Several of the trends identified in the document will be of interest to those involved with API manufacture, as well as for others involved with pharmaceuticals and healthcare in terms of general GMP observances. This article draws out the main themes.

Introduction

An API is the basic drug itself with the desired medicinal (pharmaceutical) properties. This can relate to classical manufacturing; or to materials derived from plant, animal or microbial sources. The World Health Organization definition of an API is: Any substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings [2].

Some drugs, such as combination therapies, have multiple active ingredients to treat different symptoms or act in different ways. Several years ago, it was more commonplace for the production of APIs to be undertaken by the pharmaceutical companies themselves in their home countries. In more recent years, many companies have opted to have the manufacturing undertaken at a different facility, often in a different country. Such measures have tended to be driven by a desire to lower costs. This increase in supply chain complexity has led to challenges for core pharmaceutical manufacturers, for API producers, and for regulators. This is not least because the quality of APIs has a significant effect on the efficacy and safety of medications. Poorly manufactured or compromised APIs have been connected to serious issues, such as illnesses and even death. There have been rigorous regulatory guidelines produced and more focused inspections put into place. The overall applicability of GMP for API manufacturers is set out in International Council for Harmonisation (ICH) Q7 [3].

Context

This document provides a review of data relating to inspections of API facilities that have been conducted by the EDQM between 2006 and 2018. Supporting data includes the geographical location of the inspections; whether the visits were initial or re-inspections; a summary of the outcomes; distribution of the observed deficiencies to EU Guidelines to GMP; and information relating to the frequency of the findings.

Main trends from API inspections

Geography

The first trend of interest is geographical. While many pharmaceutical companies are located in the US and UK, most API manufacturers are overseas. The largest are located in Asia, particularly in India and China. This is perhaps reflective of more companies turning to outsourcing to cut costs on expensive equipment, employees and infrastructure. This is shown in the EDQM data. The primary API manufacturers are located in the following areas (ranked in order of inspection frequency):

  1. India (~50% inspections),
  2. China (~30% inspections),
  3. Other Asian countries (~10% inspections),
  4. European Economic Area (~5% inspections),
  5. Rest of the world (US, Africa or Middle East) (~5% inspections).

As the data indicates, India and China are dominating global API manufacturing. Of these inspections, the re-inspection to new inspection rate is approximately 70:30, respectively. Care is needed when interpreting such figures, as the higher proportion of non-compliant sites could be the result of the ability of the EDQM to identify sites with higher risk of non-compliance and to focus more greatly on them.

Compliance scorecard

The data indicates that compliance rates for API manufacturers ranges from 99% (in a good inspection year) down to 60% (in a bad inspection year). The years for the poorest compliance outcomes were between 2009 and 2013, with signs of improvement from 2014 onwards. Overall, for the period of the document (2006 to 2018), the compliance rate is assessed by the EDQM as 78%.

Types of deficiencies by quality system

The main deficiencies noted across the review period are as follows.

  • Quality related (36%).
  • Building and equipment (26%).
  • Materials management, or storage and distribution (14%).
  • Laboratory controls (13%).
  • Production related (7%).
  • Compliance with licence dossier or to European Pharmacopoeia (4%).

With the categorisation of the deficiencies, the EDQM have adopted a common quality systems approach.

In terms of how these categories have altered over time, quality-related matters (at 40% in 2018) and laboratory control concerns (at 17% in 2018) have shown an increase, while matters related to licencing, production and materials have shown an improvement. That said, overall the distribution of the deficiencies is rather stable throughout the years. No detail is provided as to why quality-related matters have stepped up and why, for example, production issues are down. As it stands, this trend runs differently from reviews produced in relation to other areas of GMP, such as sterile manufacturing where production and facility issues remain high (see GMP Review 2017;16(2)) [4]. However, the analysis does show for the 2017–2018 period:

  • quality-related matters accounted for 581 observations
  • compared with 291 for buildings and facilities;
  • 228 for laboratory controls;
  • 170 for materials;
  • 114 for production; and
  • 19 for compliance with the dossier.

These findings were largely classified as ‘others’ (using the standard European approach to the categorisation of GMP issues), with 151 ‘majors’ and just two ‘critical’ observations. With this breakdown, the EDQM does point out that: “the combination of major findings may lead to an overall critical risk for public health (and therefore a non-compliant inspection outcome without individual critical deficiencies)”.

Main deficiencies

With the different quality systems, as reviewed above, quality-related matters feature most greatly in terms of non-compliances. One of the most common areas of concern within this system is with insufficient oversight of quality unit over GMP activities. This includes the following, as the report indicates.

  • Failure to effectively control documentation (both paper and electronic).
  • Inadequate overview of production and laboratory activities.
  • Under-reporting and insufficient investigation of quality events (which means complaints, deviations, out-of-specification (OOS) reports, and change controls).
  • Weak documentation practices, such as rewriting documents, untimely recording of operations, and the unavailability of records.

Also called out with the quality system are the inconsistent or inadequate application of quality risk management principles, most notably in relation to production activities, deviations and change control. In several cases of change control, the problem was found not to be a deep‐rooted practice, or something which was under-reported. A related concern was with the impact of changes not being properly assessed.

Similarly, with deviation management, often the problem is not a deep‐rooted practice; insufficient deviations are raised; deviations take too long to close; deviations are not investigated in depth (such as no root cause); proper corrective and preventive actions are not set; or an accumulation of minor deviations are not treated as a major issue (or at least not considered globally).

A further concern is that annual quality reviews are either not being undertaken or are incomplete (in that not all batches are reflected), or are not used as a quality tool by companies (such as trends not being identified and acted upon). Also, within the general concern with quality, are the following.

  • Insufficient personnel training, including insufficient training within API facilities in relation to GMP, and with no assessment of training efficiency being made or with the training programme being of limited value.
  • Validation is also mentioned as a concern with some API manufacturers, such as processes used for recovered solvents, blending or micronisation not being validated. A secondary validation concern is cleaning validation, especially where there is a lack of scientific understanding.

With materials management, the number one deficiency is insufficient approval and management of vendors of key starting materials or intermediates. The second area raised most often is the loss of traceability due to insufficient identification of containers; and third is improper storage conditions.

Regarding buildings, the primary concern is contamination ingress or cross-contamination between batches, which is reflective of both poor building and process design, and there is a link back to cleaning validation. Contamination concerns are also connected to cleaning schedules and maintenance schedules, especially where regulators have identified risks of contamination or cross-contamination.

For the production system, the issues cited relate to the blending of batches, especially when this occurs without prior appropriate testing and with a lack of control of solvent recovery.  

For the laboratory system, the highest ranked concern pertains to fraudulent practices regarding testing activities, such as pretesting or “testing into compliance”. This is followed by deleting OOS results; and a general unreliability of analytical or microbiological results. Also noted are issues with Chemical Reference Standards; with not following the appropriate European Pharmacopoeia monographs; and insufficient establishment of secondary or in-house standards. Laboratories are also called out for insufficient qualification and maintenance of equipment.

Data Integrity

A further area that cuts across the different quality audit systems is data integrity. The EDQM assesses that the majority of breaches of data integrity occur with documentation practice and in laboratory controls. Other issues have tended to be observed in relation to process and equipment validation as well as controls on computerised systems.

The most common data integrity issues are insufficient controls to prevent data manipulation and lack or insufficient review of audit trail. To add to these, inspectors have also noted an absence of management of access levels, which can cause the risk of a loss of traceability, together with a lack of sufficient controls to prevent the manipulation of data. Beyond computerised systems, other issues related to data integrity flagged include the following.

  • Falsified documents.
    • Rewriting to cover OOS or deviations.
    • Incorrect or unapproved procedures.
  • Falsified layouts/premises.
    • Hiding unacceptable parts of the facility or covering doors.
  • Falsified raw data.
    • Presenting acceptable results in place of the actual (invariably out-of-limits) ones.
    • Using “unofficial” laboratory equipment to select acceptable batches for the “official” testing.
    • Deleting OOS results and replacing by “correct” ones.

It is noticeable that 44% of critical and 25% of major deficiencies observed between 2015 and 2018 were related to data integrity issues, indicative of how the pharmaceutical sector overall continued to struggle with the subject of data governance.

Pharmaceutical companies purchasing APIs have not been immune to criticism and inspection findings either. Some common deficiencies here include the following.

  • Failure to maintain complete records of APIs.
  • Failure to transfer all quality or regulatory information received from the API manufacturer to the customer.
  • Failure to control repackaging, relabelling, and holding operations in order to avoid mix-ups and the loss of the API identity.
  • Failure to have a Quality Unit responsible for reviewing and approving current GMP documents and procedures and assuring product quality.
  • Mislabelled containers found in relation to APIs.

These pharmaceutical company issues indicate that some companies do not fully understand what is expected for their own part in relation to API GMP or do not have appropriate systems in place to comply fully.

Summary

The list of key findings from the inspection of API facilities provides background context to some of the challenges that API manufacturers are facing, as well as an indication of the current focus of European inspectorate bodies. Some of these trends show similarities to the wider pharmaceutical GMP challenges, such as the focus on data integrity. Through issuing the review, the EDQM outlined the main non-compliances pertaining to API manufacture. Here, quality-related issues constitute the main reasons for non-compliances during GMP inspections, which sends a clear signal to API manufacturers about their areas of focus as well as notifying finished products manufacturers as to the most important considerations when selecting API suppliers and topics for cross-company auditing.

References

  1. European Directorate for the Quality of Medicines Certification of Substances Department. EDQM Inspection Programme. EDQM Inspections and Trends of Deficiencies. Overview 2006 to 2018.  PA/PH/CEP (18) 56. Straßburg, Frankreich: EDQM; 2019. Verfügbar unter: https://www.edqm.eu/sites/default/files/cep_edqm_inspections_and_trends_of_deficiencies_2006_2018_pa_ph_cep_18_56.pdf
  2. World Health Organization. Definition of Active Pharmaceutical Ingredient. Working document QAS/11.426/Rev.1. Geneva, Switzerland: WHO; 2011. Verfügbar unter: https://www.who.int/medicines/areas/quality_safety/quality_assurance/DefinitionAPI-QAS11-426Rev1-08082011.pdf
  3. International Council for Harmonisation. ICH Topic Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients. CPMP/ICH/4106/00. Geneva, Switzerland: ICH; 2000.Verfügbar unter: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-7-good-manufacturing-practice-active-pharmaceutical-ingredients-step-5_en.pdf
  4. Sandle T. MHRA annual deficiency review highlights sterility assurance issues. GMP Review 2017;16(2):4-7.

Author:

Dr. Tim Sandle (tim_sandle@bpl.co.uk) is Head of Microbiology at the UK Bio Products Laboratory. In addition, Tim is a visiting tutor with the School of Pharmacy and Pharmaceutical Sciences, University of Manchester. Tim serves on several national and international committees relating to pharmaceutical microbiology and cleanroom contamination control. Outside of work, Tim runs an on-line microbiology blog (www.pharmamicroresources.com) and he has written extensively on the subject of pharmaceutical microbiology and contamination control.


Excerpt from gmp review

This article, “EDQM inspections and trends of deficiencies relati”, is reproduced from a recent issue of gmp review, a quarterly journal researched and edited by an expert team experienced in all aspects of pharmaceutical manufacturing and control.

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