The Importance and Impact of The Cleaning Process

Cleaning has always represented a big challenge in the pharma industry. Regrettable events that have led to the loss of human lives have forced us to remember that avoiding cross contamination by every means is always a necessity in the industry.

It is an absolute that no risk of any type can be allowed because, instead of solving health issues, we would be generating events that can cost lives. Just remember the case of the dirty 200kg containers used to package tons of a raw material, that were literally shipped worldwide. These turned out to be contaminated with residue from petroleum derivatives because the cleaning of the containers was not assured.

It took several cases like this before the world’s regulatory authorities established basic rules to guarantee that medications manufactured with raw materials and materials that are used to manufacture and package medicines are safe, pure and effective.

It is for this general reason that regulatory agencies expect manufacturers to develop and validate an integral and complete general cleaning program; in fact, the cleaning process is considered a critical system within the industry, which is why the risk of contamination, residue carryover from products, and any type of cross-contamination must be monitored, controlled and minimized to safeguard the security of patients and the quality of the product. An integral part of an effective cleaning program is using a risk-based approach, both for the design and for the good management of the cleaning validation; at the end of the day, the most important factor is to design cleaning programs that are compatible and effective. We must not lose sight of the fact that validated cleaning is a requirement that applies to these industries: biotechnology, biological, pharmaceutical, diagnostics, nutraceuticals, medical devices and even cosmetics.

The main purpose of cleaning validation is to prove the effectiveness and reproducibility of the cleaning process for production equipment and/or related parts, to prevent the cross-contamination and adulteration of medications or biological products, whether by another active substance, chemical agent, or unwanted compounds (for example, active ingredients, residues, excipients or detergents), or from microbiological contamination. This includes establishing criteria to reduce risk in patients by producing medications that meet the criteria of quality: that they are safe, pure and effective.

The processes of cleaning and their validation have evolved so much that, today, a broad number of segments have incorporated these processes, including:

• Research and development, since they establish the manufacturing processes and, therefore the cleaning of equipment and areas, as well as defining the chemical agents for cleaning.
• Toxicology, since there are substances with high pharmacological activity, which is why it is imperative to determine the limits of allowed exposure and acceptable daily exposure (ADE).
• Engineering and maintenance, since they are heavily involved in the design of the equipment and their respective maintenance and cleaning.
• Production and validation, which are the ones that operate the equipment, mount and disassemble pieces, solve operational and maintenance problems, as well as execute tests and report the validation protocols.
• Control and quality assurance, which are the groups that perform samplings, laboratory studies, analytical method developments, and monitor the compliance of the GMPs.

The existing regulations in several countries are aligned with general principles that arise from the basis that all pharmaceutical products must be safe, effective and free from adulteration from other components or pollutants. The guides and regulations of reference used have been developed by countries and advanced international organizations, such as:

            - CHP&FBI Guidance - Canada

            - EMA - European Union (European Medicine Agency)

            - FDA (Food and Drug Administration - USA)

            - ICH (International Conference of Harmonization)

            - PIC/S (Pharmaceutical Inspection Cooperation/Scheme)

            - OMS (World Health Organization)

Likewise, there are existing pharmaceutical documents and guides developed by experts within the pharma industry, such as APIC, ASME, BPE, ASTM (several), ISO 13408, ISPE and PDA.

The most important aspect that the manufacturers of medications need to establish is the limits of residue acceptance, and the criteria must be defined based on the type of substance; that is to say, if the residue comes from highly dangerous compounds, meaning compounds with a low daily exposure acceptance (ADE), for example =<10 mcg/day, a specific analytical method must be used to quantify the residue (HPLC) and to establish the maximum allowed carryover (MAC). The best examples are psychotropics and oncological medications.

In the case of non-hazardous compounds, these refer to compounds with an ADE >= 100 mg/day; in these cases, the PDE corresponds to a dose of a specific substance that is unlikely to cause any adverse effects to a person is that individual is exposed every day of his life to the these expressed doses or less. In the case of a substance that is going to be cleaned in the manufacturing equipment, then it’s possible to consider the use of non-specific analytical methods to be used for residue quantification, as is the case of the Total Organic Carbon (TOC), and thus establish a safety limit.

Frequently the actors in the pharma industry ask, what are the references that indicate that a non-specific analytical method could be used to determine the residue? Here, we have included all of the official and guild references that exist in that regard; however, the most important issue is to develop the scientific rationale that supports the decisions made to use non-specific analytical methods. If we are dealing with a non-dangerous compound (with an ADE value equal to, or greater than 100mg/day), and the residue is not going to generate long-term adverse effects, there is total justification supporting the usage of TOC as a non-specific analytical method. If we add the advantages of the non-specific method, which is cheaper and faster, robust and sensitive enough, measures within the expected range, and is able to quantify and add the residues from the degradation of the active ingredients, excipients, and detergents, even if it is non-specific, it will be appropriate and sufficient to be able to achieve the objective of an effective cleaning process.

We have shared in different forums our successful experiences running correlation tests, where an active substance is quantified by HPLC and TOC in parallel; if the results demonstrate that similar results are obtained with both analytical methods, with  statistical support ⁠— evaluated by experts in pharmaceutical statistics ⁠— then they already have in hand the necessary  “scientific rationale” required to demonstrate before any regulatory agency and justify the use of non-specific analytical methods for cleaning validation.