Microorganisms are everywhere — in the air and water, on skin and other surfaces. When microbiological contamination occurs in manufacturing, drug product batches are wasted, risking potential recalls and plant shutdowns. Results include lost time and money for manufacturers, drug delays and shortages, and related loss of public confidence, potential fines — even criminal consequences.

With so much at stake, drugmakers, their contract manufacturing organizations (CMOs), and industry regulators increasingly need to look into microbiological Environmental Monitoring (EM) to help ensure that life science products, facilities and water meet safety and efficacy standards for public health. EM has become critical, especially in recent years as some manufacturers have faced increased scrutiny and tough consequences related to contamination. According to a recent Forbes article, “Increased Justice Department scrutiny represents a shift from past government enforcement approaches where the U.S. Food & Drug Administration (FDA) took the lead initiating investigations of pharma manufacturing plants for violations of good manufacturing practices (cGMPs).”¹

The FDA requires all pharma manufacturing companies to have EM standard operating procedures (SOPs) in place as an important part of the drug release process to ensure public safety. To maintain production, license holders must prove aseptic manufacturing processes as part of the current Good Manufacturing Practices (cGMP) requirement of 21 CFR Part 211.188.²
The FDA’s rules for trending and identifying contamination sources apply to CMOs and generics producers as well — both of which continue to grow in number. Warning letters have specifically been issued to companies that lack adequate systems for monitoring environmental conditions in aseptic processing areas and for not having written procedures for EM — including sampling frequency, sampling locations and procedures for alert and action levels.

Industry best practices can help shape SOPs to develop and deploy EM programs and avoid  warning letters. However, many well-intentioned EM programs fail to live up to their full potential. There are three significant challenges related to EM: a plethora of error sources, inefficient processes, and the identification of (potential) contamination sources due to the inability to collaborate effectively. Overcoming these hurdles by leveraging existing information, the right insights, and suitable technology can put manufacturers on a path to better EM program success.

Environmental Monitoring’s Complexities
EM, by definition, includes interval, ad-hoc and event-driven collection and testing for microbial (bacteria, viruses) and particulate contamination as shown in Figure 1. Sampling occurs in sterile manufacturing rooms, where products are mixed, dispensed, handled and packaged including all surfaces and apparatus used, as well as the air itself. Water for injection (WFI), used in the product or as part of the aseptic process is sampled, along with product ingredients or finished product selected randomly after sterilization has been applied (e.g. autoclave, gas, filtration, etc.). Workers’ clothing, gloves and masks also must be sampled and tested to ensure humans are not breaching the integrity of the sterile manufacturing process with bacteria, hair or dust, which are the main sources of contamination in clean rooms.

On a practical level, EM requires managing complex schedules for collection and analyses for thousands — even tens of thousands — of samples per month. Gathering required samples to check for microbial (bacteria) and fungal (mold) growth consists of swiping floors, apparatus and personnel. Agar plates are left open in the process room or touched to surfaces, and then incubated and read for growth. Air sampling is conducted to check for airborne viable (microbial/fungal) or non-viable (particulates such as dust, skin and other contaminates suspended in the room air). In addition, sterile water lines, product ingredients and finished products are randomly selected for sampling.

Additional interference of management personnel and according actions are required for out of specification (OOS) and out of trend (OOT) sampling test results and for missed samples — which potentially must be reported internally and even to the FDA. Organizations ideally have procedures in place to adapt testing intervals, perform investigations to determine the source of “positive” growth, perform cleaning and validation (re-verification of sterile condition), quarantine products and even shutdown manufacturing lines when deemed necessary.

Such complex procedures with thousands of variables translate to the three challenges commonly found in EM programs. Solving these problems with technology solutions —including software to automate data collection and management — helps elevate EM programs to a more advanced manufacturing success level that adds value in addition to contamination prevention.

Challenge #1: Error-Prone Processes 
Quality improvements help CMOs to differentiate their services. Knowing that errors in EM programs can threaten compliance, impede quality and hinder productivity, a reliable system is critical for outsourcing. Quality and compliance benefits come into play when paper systems go away. Whether a contract manufacturer is collecting data to share with a customer’s Quality team, or a drug patent owner is reporting to regulators, simpler access to millions of electronic sampling records can eliminate what is otherwise a tedious and inefficient process.

Adopting electronic EM systems leads to less error-prone processes and, therefore, higher quality that CMOs can promote. For drug sponsor companies this translates to security. Implementing an electronic sampling plan and instituting bar coding, for example, are two ways errors can be reduced or eliminated. A CMO with such systems in place demonstrates to customers it is taking EM and safe productivity seriously.

A sampling plan defines both the frequency of sampling and the locations to be sampled. Planned sampling dates are then represented in an interactive calendar view that facilitates rapid workflow processing and prevents from missing any samples.
Automated scheduling, sampling, testing, incubation, and results-entry for quality control programs: these guide the user and prevent process deviations that can lead to errors or missed information associated with hand-written notes.

EM sampling plans tell exactly what steps should be taken and when, specific to location and other parameters. The electronic system (as shown in Figure 2) is set up to manage risk with rules and procedures in electronic form, which is much less error prone than paper and manual handling of schedules. Adding bar codes to sampling further assists with tracking and helps manage complexity. For example, in second incubation phases, samples may have different types of air and surface measurements. Bar coding helps to link a sample to its location and sampling point — avoiding mix-ups, because information is tracked in electronic records. Errors are reduced and time required to enter manual data is saved. With a less error-prone sampling system in place, EM becomes a quality enhancement feature rather than a cumbersome program.

Challenge #2: Inefficient Processes 
Once the necessary EM processes are in place, companies need to focus attention on reducing cycle times, as EM testing tends to be a bottleneck for product release. A good starting place is identifying non-value-added steps that are hindering productivity. Relying on paper-based systems and/or data logged into different systems (e.g., Excel spreadsheets and written notes) can be a primary cause of inefficiency.

Think back to the aforementioned thousands of samples resulting in millions of data collected and measured each year, and imagine all of that related data housed in disparate paper records and spreadsheets. It paints a troublesome picture of how much time is wasted entering those data and retrieving them when required. Electronic solutions for data capture and storage help automate processes, ultimately saving time and improving manufacturers’ ability to spot trends and identify sources of contamination.

In an electronic EM system, a sampling plan will be scheduled electronically and sample-related data will be entered automatically through scanning of barcodes. This will also allow easy tracking of samples throughout their life cycle. Electronic data transfer from devices can be validated and documented and will ensure there is no source of error.

The data review in an electronic EM system is simplified by eliminating manual processes that would need to be verified.
Automated alerts streamline the review and approval process by “review by exception.” So when the system identifies data outside of specified ranges, it flags the appropriate data and reviewers only have to focus on these entries knowing that something went wrong. They won’t need to look into data within specification but can focus only on the “exceptions,” and investigations can begin — possibly preventing contamination.

For CMOs, cost savings result from eliminating non-value-added steps in their EM processes and from avoiding shuffling paper back and forth with sponsors. Saved time equates to fewer man-hours and saved costs, enabling more batches to be produced on the same equipment. Ultimately electronic EM systems help CMOs to remain competitive.  

Challenge #3: Ineffective Collaboration
Whether working across global sites, with CMOs or across Quality teams at one manufacturing location, collaboration has to be both enabled and effective. EM programs that do not have an efficient mechanism built in for communicating reports, data and actionable intelligence make it difficult to collaborate, and, therefore, challenging to improve quality and compliance across an organization.

All data captured in an electronic EM system help provide on-demand reporting, tracking, trending, and visualization of critical information without exporting and reformatting paper-based data. For example, product quality can be compared from one site to another. When something changes in a manufacturing process, captured data may become relevant to contaminated products and root cause investigations.

With a paperless EM system in place, all relevant information can be easily provided to support collaborative decision-making. If a customer requests data related to environmental monitoring of a manufacturing process, a CMO with easy access to sharable, searchable data avoids the time required to dig through paper records — and scores business relationship bonus points.

For global executives in manufacturing, Quality Control (QC), Quality Assurance (QA) and IT — as well as for site managers and managers in the lab, the manufacturing plant and tech support — EM becomes a critical aspect of success. Collaborating across organizational boundaries and sponsor/CMO relationships in the name of better drug quality and minimized business risks is paramount.

While many EM programs are well intentioned when institutionalized, without the right automation in place they often don’t provide the expected success, because users rely on spreadsheets and solutions that feed the top challenges associated with EM. Evaluating processes and harmonizing EM with an electronic, paperless system brings organizations further in line with FDA regulations and cGMPs by eliminating sources of error and allowing for easy trending and problem prediction. Additionally they are improving productivity, reducing cycle times and strengthening sponsor-CMO collaboration. 

References

1. Kelton, Erika, “Filthy Pharma: Justice Department Taking «Especially Hard Look» At Manufacturing Plants,” Forbes.com, June 6, 2013.
2. 21 Code of Federal Regulations Part 211 – CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS http://www.gmp-compliance.org/guidemgr/files/1-1-1.PDF

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Daniela Jansen, Ph.D., is product marketing manager at Accelrys, a provider of scientific innovation lifecycle management software. She has more than 20 years of experience in laboratory and informatics and instrumentation, with expertise in 21 CFR Part 11 compliance and Lean Six Sigma in life sciences. She is based in Germany and can be reached at daniela.jansen@accelrys.com.