Contamination control measures are one of the basic requirements for the manufacture of medicinal products. Pharmaceuticals manufacturing requires a defined and valid system to avoid contamination, as well as a clear disaster strategy to handle any microbiological deviations.
Normally, one would expect that awareness of these activities is programmed into everyone working in the Good Manufacturing Practice (GMP) field.
However, a quick look at the inspection report summaries by the responsible authorities reveals that between 1995–2005, potential risk of microbiological contamination was the No.2 Critical GMP Deficiency and No.1 Major GMP Deficiency observed during inspections ordered by CHMP/CVMP.
This shows that in Europe, contamination control remains a topic of importance. A detailed analysis of the annually published FDA Inspectional Observation Summaries (483s) also shows that issues such as hygiene, cleaning and disinfection were also frequent reasons for deviations.
More than 120 entries in the Fiscal Year (FY) 2010 Inspectional Observation Summaries demonstrate that this is not only a European issue.
FDA Warning Letters in following years indicate that the situation improved. In 2013 section (§) 211.113 of the Code of Federal Regulations (CFR) did not show any respective citations of hygiene deviations in the top 10 rankings of the most frequent GMP deviations.
However, any expectations that this development would continue, proved to be wrong. An analysis of the FDA Warning Letters of FY 2014 shows that number one in the 21 CFR 211 Citations – Top 10 List of Finished Pharmaceuticals, is § 211.113 – Control of microbiological contamination; number eight is § 211.67 – Equipment cleaning and maintenance, and number nine is § 211.56 – Sanitation.
Furthermore, inquiries from contamination control course participants and online discussion forums show that people still need information on basic issues of contamination control, such as:
- Choice and validation of disinfectants
- Factors for selection of the right cleanroom garment
- Gowning procedures
- Monitoring of success control of contamination control measurements
- Handling and analysis of deviations
Moreover, a frequently asked question is: Where in the regulatory documents are all these things defined? And thus budgets are quite frequently only approved if requests for implementing necessary actions can be substantiated with regulatory requirements.
Several guidance documents are available that include information about regulatory expectations or state-of-the-art contamination control:
- EU GMP Guideline
Annex 1 ‘Manufacture of Sterile Medicinal Products’
- FDA Guidance for Industry ‘Sterile Drug Products Produced by Aseptic Processing’
- l IS0 14644 – DIS (2010) Classification of Air Cleanliness by Particle Concentration
- l ISO 14698-1, Cleanrooms and associated controlled environments – Biocontamination control, Part 1: General principles and methods
- l ISO 14698-2, Cleanrooms and associated controlled environments – Biocontamination control, Part 2: Evaluation and interpretation of biocontamination data
- National Medicinal Product Acts
- Pharmacopoeias
- ICH Guidelines (e.g. Q9 -> Quality Risk Management)
- ISPE – Baseline Guides (e.g. Sterile Manufacturing Facilities).
However, these documents also provide more non-specific guidance, such as the EU GMP Guideline chapter 3:
‘Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products’
3.2 ‘They should be cleaned and, where applicable, disinfected according to detailed written procedures’
3.4 ‘Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals’
3.9 ‘Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection’
These examples show that there is no off-the-shelf ‘recipe’ available for a suitable contamination control system.
The first step will be that the responsible persons ensure that they are fully familiar with the related rooms, technical equipment, containment and manufacturing processes.
This will be the base for the second step – to analyse the possible risks and sources of contamination, define critical steps in manufacturing and identify the critical control points.
Analysing risks
Risk control includes making decisions to reduce and/or accept risks, for example:
- What is an acceptable risk level?
- What can be done to reduce or eliminate risks?
- What is the appropriate balance among benefits, risks and resources?
- Are new risks introduced as a result of the identified risks being controlled?
The results of such an analysis – regardless of whether a system such as FMEA (Failure Mode and Effects Analysis) or HACCP (Hazard Analysis and Critical Control Points) or another was used – will then provide the basis for the definition of the necessary actions and the corresponding data, which should be included in the hygiene plan and the related SOPs.
This includes:
- What to do – necessary actions
- Who will do it
- How to do it
- Necessary equipment
- How often
- Controlling responsibility
An example will be the ‘Minimum Cleaning /Disinfecting Frequency’ as shown in Table 1.
Table 1: Minimum Cleaning/Disinfecting Frequency based on cleanroom class, work frequency, waste Volumes, operator Numbers, introduced materials and resulting risk evaluation
| Surface | A/B | B | C | D | E/F |
|---|---|---|---|---|---|
| Waste bin | na | d | d | d | w |
| Washbasin | na | d | d | d | w |
| Light switch/doorknob | d | d | d | d | w |
| Work surfaces | d | d | d | d | w |
| UAF – laminar flow – side walls | d | d | d | d | na |
| Steel grating | na | na | w | w | w |
| Trays, cupboards (outside) | na | w | w | w | w |
| Sterilisers (outside) | d | w | w | w | w |
| Fixed tanks (outside) | na | w | w | w | na |
| Floor gully | na | na | 3/w | 3/w | w |
| Floor | d | d | 3/w | 3/w | w |
| Doors | w | w | m | m | m |
| Pipes | w | w | m | m | h |
| Walls windows | w | w | h | h | h |
| Lighting | m | m | h | h | h |
| Ceiling | m | m | h | h | h |
And, if all these things are analysed and defined, there will still be no time to relax. It is necessary to pay constant attention because experiences in the past have shown that sometimes small changes can disrupt the contamination control chain.
To track a system, a monitoring strategy is inevitable and it should cater for occurrences such as that given in the example in the panel.
Example of how a good hygiene system was interrupted but detected by monitoring
A manufacturer that had operated for a long period with a hygiene system that had worked well, suddenly detected spore forming bacteria. First it checked for contamination in the air systems, but all filters were ok. A check of the garments was negative, and so was a check as to whether some packaging materials were the source of the contamination. The responsible person then began to evaluate whether something had changed – materials, process steps, suppliers, etc. He found that the supplier of the paper towels at the hand wash basins had changed. The towels being used were no longer bleached for ecological reasons; purchasing had switched to recycled paper towels that contained bacterial spores.
This example shows that the implementation of change control procedures is an important tool to keep an existing system effective.
Additionally, it is clear from the example that communication between different departments, such as quality, production and procurement, is essential to achieve and maintain a suitable contamination control system.
An additional need is that the people involved – from the responsible QA/QC staff, to the cleaning personnel and the people collecting the monitoring samples – are well trained in their roles. Without a correct performance of steps such as surface disinfection, the reduction of microbes will be insufficient.
Furthermore, if monitoring samples are taken without proper care, false positive samples will be the result.
In summary, this article shows that GMP compliant contamination control requires more than ‘a bit of cleaning’. It necessitates a lot of knowledge to carry out the risk assessment, have an overview of critical points, define the contamination control steps, the corresponding monitoring and at the end to analyse the monitoring results and handle deviations.
The analysis of the collected data during the monitoring is especially essential to identify trends and, in this way, to get the chance to react before deviations happen. Therefore well-trained operators in cleaning, manufacturing and sampling are a basic requirement.