Probiotec

Having completed my bachelor of science in biotechnology back in 1992, I immediately planned to be on a plane with my friends on my way to the Bahamas to think about career and what I wanted to do with my life. However, before I could reach the airport and get onto that plane, I was offered a role for a small start-up company in the quality control lab. Believe it or not, I had not even applied for the job. It came to me through a friend. I cancelled my ticket, and my holiday was over in minutes. I was going nowhere! My destiny was being set. I was going into pharmaceutical manufacturing.

The business I worked for was a start-up company involved in manufacturing sport/health/nutrition products. I entered a small lab having only a small HPLC unit with a chart recorder and some basic wet-type chemistry applications. I knew nothing about GMP. I knew nothing about pharma.

GxP came to me unexpectantly! Given the company was making therapeutic claims on their labels, our national regulatory agency stepped in requesting that products undergo registration and the site be licensed as a manufacturing and packaging facility. This was all a shock to everyone, as no one knew where to start, or where to go, or what was involved.

As the old saying goes, ‘throw them in the deep end and you are left with 2 options: Sink or swim…!’ I had no choice but to swim. Now I was on my way to learning pharma--start to end!

Stability trials, cleaning validations, documentation, deviations, OOS’s, CAPA’s, PQR’s etc. I was treading water--only just--then I began to swim! I was learning!

31 years later, and I’m still learning every day. Having gained experience in sterile and non-sterile products consisting of oral solid dose preparations, vaccines, antivenoms, blood products, antibiotics, hormones, chemo-therapy drugs etc. and having worked overseas in clinical trials for several years, I have gained the knowledge and insight into GxP’s and the expected industry standards from those compared from yesteryear. Furthermore, working with regulatory agencies such as the FDA (US), KFDA, EMA, TGA has provided me with an insight into the increasing demands on pharma industries.

As with many things, one area which I have seen evolve over the years is ‘cleaning validations’ and the regulatory expectations to assure consumer safety and product efficacy.

Over the years, I came to see cleaning becoming closely associated with ‘process validation.’ In the early 90s, regulatory agencies began to view cleaning as a process that needed to be validated. At the same time, several safety incidents involving cross contamination solidified this viewpoint. Therefore, many companies set about validating their existing cleaning procedures without questioning whether the procedures utilised were the most effective or optimal, or even if they were using the appropriate cleaning agents and detergents.

Traditionally, (back in my early days), cleaning validations incorporated a pre-approved protocol, with predetermined acceptance criteria and a ‘three-run’ process validation approach. This being typical across the industry. Because of this traditional approach, the industry also struggled over how to set the required predetermined acceptance criteria. This process validation approach was adopted without ever asking if three cleaning validation runs and predetermined acceptance criteria were appropriate for the validation activity. Based on this reasoning, Annex 15 (section 10) came into existence stating:

“The cleaning procedure should be evaluated an appropriate number of times (based on a risk assessment) and meet the acceptance criteria to prove that the cleaning procedure is validated.”

The cleaning of manufacturing equipment to prevent cross contamination of pharmaceutical products is a fundamental aspect of GMPs. Validations of these cleaning procedures has been required within cGMP for as long as I can remember and is recognized as an important activity to establish that product cross contamination is controlled to ensure patient safety and product quality.

"By implementing a truly science-based approach, such as the use of appropriate risk assessments, a streamlined cleaning program may be readily developed that ensures patient safety and product quality while lightening the regulatory burden on industries"

While the actual act of ‘cleaning’ is a relatively simple process, the pressures of inspection and scrutiny by regulators have transformed these activities into a complex, expensive, and time-consuming process. I personally have experienced projects consisting of multiple products, multiple pieces of equipment, and multiple cleaning procedures which extended out into years.

Like always, companies seek to gain efficiencies and cost savings. Thus, many companies have made various efforts to reduce cleaning activities, such as dedicating equipment or converting to disposable items. However, these strategies have their own inefficiencies and costs. Companies have also resorted to strategies such as product grouping, equipment grouping, matrixing, and bracketing to reduce the amount of cleaning they validate, sometimes without acceptable justification.

Many companies today validate the cleaning of only one or two ‘hardest-to-clean’ products, selecting them based on the solubility of the API or because the calculated limit is lowest, even though these may not be truly justifiable criteria. The EU guideline ‘Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use,’ Annex 15 outlines in Section 10 the following:

‘For a worst-case product approach, a scientific rationale should be provided.’

Since 2001, there have been many new concepts introduced due to high expectations by regulators. Examples include:

• GMPs for the 21st Century
• Quality by design (QbD)
• Process analytical technology (PAT)
• FDA 2011 guideline on process validation.

Globally, the new International Conference on Harmonisation’s guidelines (ICH), in particular Q8 and Q9, are some of the major forces driving change in the industry. Movements within pharmaceutical manufacturing itself have seen the rise of:

• lean manufacturing
• Six Sigma
• operational excellence (OpEx)

To this end, cleaning validation are based on science, risk, and statistics. It offers a clear direction of making sensible changes and decisions with the cleaning process, that would reduce the complexity, lower the costs, and shorten the process while providing a high probability that the cleaning of manufacturing equipment has been effective. By implementing a truly science-based approach, such as the use of appropriate risk assessments, a streamlined cleaning program may be readily developed that ensures patient safety and product quality while lightening the regulatory burden on industries.

Like I keep telling my fellow work colleagues, we learn something new every day.