Working with clients to assist in bringing innovative, safe new medicines and medical devices to patients in need.GET A QUOTESAMPLE TRANSMITTAL FORM
‘Our Mission is to work with clients to assist in bringing innovative, safe new medicines and medical devices to patients in need.’
Pine Lake Laboratories is a small GLP/GMP compliant analytical and bioanalytical contract testing laboratory that is FDA registered located in Bristol, CT. Pine Lake Laboratories has extensive experience with method development and validation and specializes in early development work. Pine Lake Laboratories has the capabilities to help pharmaceutical, medical device, and contract manufacturing companies get their product to market faster and more efficiently.
Contract Research Organizations that promote “one stop shop” services with various locations are competitors and are sometimes chosen as the ‘safe option’ due purely on total number of resources. However, choosing a large scale CRO comes with problems of its own; stakeholder ambiguity, increased regulatory scrutiny, and ridged bureaucracy.
Small or midsize projects become less of a priority to companies with the most purchasing power. We give unwavering service across the board, no matter your size or name.
Choosing a smaller contract research organization comes with advantages; flexibility, swift decision making, personalization and communication. There is no barrier between client and President of the company, or large steps from sales to scientist. All employees have a voice and can help the client succeed in getting their product to market safely.
Pine Lake Laboratories understands that the industry is continuously growing and innovating. We strive to be as flexible and adaptive for our clients because we know they are fully immersed. For example, a client may be informed by their vendor of a upcoming material change in the bio-processing system and we will pivot our study plan accordingly for this new material.
Moreover, being a small business, we accept projects that can be seen as a “risk” to large companies; a project that takes a lot of resources due to it being more ‘experimental’ in nature. Pine Lake Laboratories will listen to your companies needs and use our expertise to come up with workable solutions to meet your budget and your teams’ goals.
Pine Lake Laboratories is a dedicated partner in all of the projects we work on and we will remain fully engaged until our customers are satisfied.
The pharmaceutical industry is constantly changing, from new ideas, regulatory guidelines, and best practices. Large CROs could have a hard time adjusting to change, small CROs don’t focus on the high throughput, rinse and repeat strategies. Pine Lake Laboratories will go the extra mile for your product, they have the instrumentation and knowledge to complete your testing and create a data package that can be submitted directly to the FDA.
All customer requests are explored and only accepted if we bring value to a project. Each client is given a personalized study design that will satisfy all their goals for their product. If a service is needed that Pine Lake Laboratories cannot fulfill, we can either outsource or make a referral to an appropriated trusted partner so that our client has piece of mind.
Furthermore, we are able to adapt new study designs quickly and smoothly with our well versed cross-trained experts and all without the unproductive layers of red tape.
Employees from Pine Lake Laboratories come from diverse scientific backgrounds. They bring experience from both small and large pharmaceutical and biotech companies. Pine Lake Laboratories is confident in our abilities to bring the correct technical expert to the discussion table to provide our clients with a full range of GMP and GLP analytical solutions.
All of our employees are dedicated to establishing trust, integrity and delivering results required to build lasting client relationships. Clients can be assured they will not just be another number with Pine Lake Laboratories.
Moreover, Pine Lake Laboratories specializes in services such as CMC Analytical, Extractables and Leachables, Bioanalysis and more. Our equipment required for our service offerings is state of the art. Moreover, our employees are not siloed into just one technique.
All employees participate in the continuous learning program at Pine Lake Laboratories, in order to refresh or educate all employees on leading industry practices. Not one scientist is a specialist on one service or instrument; they are all experts, highly trained on all services and instrumentation.
At Pine Lake Laboratories our clients are treated as coworkers. We take time to understand their goals and mission. Their mission statement becomes a part of ours; clients can express their visions, struggles, and outlooks. A call or visit from the President of Pine Lake is only a simple request away and easily accommodated. Dr. Kurt Moyer is happy to visit clients’ offices to meet project teams and fully explain the capabilities and services Pine Lake Laboratories has to offer. Furthermore, visits to Pine Lake Laboratories are also welcome- before or during projects. Clients may want to take a tour of the facilities, meet the team, conduct an audit, or visit during a specific milestone of their testing.
Pine Lake Laboratories makes every step of the process as painless as possible; from quote generation to final report. Again, they can easily speak with our key employees to get any answers to their questions.
Pine Lake Laboratories is a GLP/GMP compliant analytical and bioanalytical contract testing organization that has the capabilities to solve even the most challenging of analytical problems by partnering with our clients, being adaptive, innovative and accommodating, as each client is a valuable member of our team.
During manufacturing, medical devices are exposed to a wide range of processing agents and materials. Depending upon the medical device, residual levels of these processing agents and materials pose a potential toxicological risk to patients. Therefore manufacturers of medical devices need to identify and properly control for contamination of the medical device from processing agents and materials encountered during the manufacturing of the device. This is done by validation of the cleaning of the medical device.
For the validation of the cleaning of a medical device, a cleaning limit needs to be established for each residual processing agent. The cleaning limit is the level below which the residual processing agents pose no risk to the patient. Traditionally this is done by performing a toxicological assessment following ISO 10993-12 on each individual processing agent (and each component of a processing agent if it is a mixture) and setting a cleaning limit for each chemical. When the total number of possible chemicals from the processing agents is small (less than 10) and all have toxicological data available, this is the preferred approach. Unfortunately, this is commonly not the case. If the manufacturer is faced with a large number of potential chemical residues from the processing agents (greater than 10), the time and cost of a complete toxicological assessment to set the cleaning limit of each component may be prohibitive. Also, complete toxicological data may not be available in the literature which could prevent the determination of the cleaning limit for a specific compound.
At Pine Lake Laboratories, we have developed an approach to assist medical device manufacturers when faced with the challenging task of setting cleaning limits for a large number of potential contaminants from process agents or when complete toxicological data is not available. Our approach is to set a worst case scenario cleaning limit and then testing the medical device by a battery of sensitive analytical techniques to determine which of the potential contaminants are actually present on the device at a level that could potentially present a risk to the patient and eliminating from further evaluation any contaminants that are present at levels that present no risk to the patient.
The Quality System Regulations from the US FDA capture the requirement for medical device manufacturers to validate the cleaning of the medical device by stating that each manufacturer shall (1,2):
Establish and maintain procedures to prevent contamination of product by substances that could be expected to have an adverse effect on product quality.
Establish and maintain procedures for the use and removal of manufacturing materials to ensure that it is removed or limited to an amount that does not adversely affect the device’s quality.
As should be obvious, any residual processing agent that presents a toxicological risk to the patient would adversely affect the quality of the device.
In addition to the FDA QSR, ISO 13485 requires the establishment of documented cleaning specifications for a medical device if any of the following apply (3):
As can be seen, both sets of regulations require cleaning validation for certain types of medical devices and manufacturing practices.
Review Process Flow to Identify the Manufacturing Materials
Before starting cleaning validation, the manufacturer needs to identify all of the manufacturing materials and processing agents that contact the medical device. This is done by evaluating the complete manufacturing process from beginning to finished product.
The manufacturing materials and processing agents can be broadly categorized into the following groups:
The end result of the process review should be a complete list of all possible contaminants that could be on the device.
The manufacturer can perform a risk analysis to determine the likelihood of each processing agent remaining as a residue on the medical device. For example, consider the following hypothetical process. A medical device is exposed to chemical A in the first step of the manufacturing process and chemical Z is introduced in the last step. After the medical device is exposed to chemical A, the medical device undergoes 3 steps in the manufacturing process that are likely to wash off chemical A before the device is exposed to chemical Z. Therefore, chemical Z is much more likely to remain as a residual than chemical A. In this case, the manufacturer could use this risk assessment to focus more on chemical Z during the cleaning validation following proper documentation of the risk assessment.
Determination of Worse Case Scenario Cleaning Limits
After the potential hazardous contaminants from the manufacturing process have been identified during the risk assessment, the acceptable level for the contaminants is determined. Ideally, a toxicological assessment should be done for each potential contaminant. However, if a large number of potential contaminants have been identified, the time and cost of a complete toxicological assessment may be prohibitive. In this case, the determination of a worst case scenario cleaning limit is recommended.
To determine a worst case scenario cleaning limit, a level needs to be determined below which even the most toxic contaminants would not present a risk to the patient. Unfortunately, the Quality System Regulations and guidances from the US FDA do not provide any assistance in evaluating the toxicological risk of contaminants on a medical device. However, guidelines from the pharmaceutical industry do pertain to establishing thresholds for patient exposure and can be applied to this situation.
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has issued a guideline titled “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” (M7). The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive and mutagenic impurities taken in by patients to limit the carcinogenic risk. In ICH M7 can be found the Threshold of Toxicological Concern defined as follows (4):
“A Threshold of Toxicological Concern (TTC) concept was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects”.
The TTC (expressed as µg/day) represents the level below which intake of a potential compound would not present a significant carcinogenic risk to a patient. In ICH M7, the guidance also accounts for acceptable higher daily intakes for shorter exposure periods. The recommended TTC by duration of treatment from the ICH M7 guideline are as follows (4):
These acceptable intake levels are based upon exposure and are determined for mutagenic compounds. Mutagenic compounds represent the worst case scenario for toxicity; therefore any compound below these levels for the listed duration of treatment would present no toxicological risk.
Although these recommendations were developed for pharmaceuticals, the acceptable daily intakes are only based upon toxicity and the daily intake by the patient. Therefore a manufacturer of a medical device could use these levels based upon the intended exposure of the patient to the medical device.
The TTC could then be used to calculate a worst case scenario cleaning limit (CLwc) for all individual potential contaminants as follows:
Where elution time is the time required for 100% of the individual potential contaminant to elute from the device into the patient and the number of devices is the expected total number of devices used on the patient. Since the elution time is most likely unknown, the worst case scenario would be for entire amount of the potential contaminant to enter the patient on first exposure, so 1 day is used as the elution time for the CLwc. If the number of devices is variable, a realistic estimate of the largest number of devices is used. The final units for the CLwc are µg /device. Instead of the number of devices, an amount of device (i.e. weight, surface area, length, etc.) can also be used.
Once the CLwc had been calculated, the medical device is tested for residual process contaminants from the manufacturing process.
Analytical Testing for Residual Processing Agents
An analytical testing strategy needs to be developed that will detect all of the processing agents identified in the risk assessment of the manufacturing process. While the analytical testing strategy will need to be specific to the manufacturing process and the medical device, each analytical testing strategy will include the following steps: washing the residues from the medical device, testing the washes for the processing agents, evaluating the results against the CLwc, and setting compound specific cleaning limits.
1 . Washing the medical device
The first step is to wash the medical device in solvents that are expected to dissolve the processing agent. The residual processing agents are likely to have varying polarities, therefore more than one solvent will probably be needed. Usually water and an alcohol, like Isopropanol, will be sufficient but other solvents may be appropriate based upon the expected residual processing agents. The solvents selected and the conditions should be appropriate for the purpose of washing contaminants from the surface without being so aggressive as to dissolve or cause leaching from the medical device.
2. Analysis for Residual Processing Agents
The washes are then analyzed for the residual processing agents. The analytical methods will be selected based upon the residual processing agents with the following analytical methods being commonly used:
3. Evaluation of Results
At the end of the analytical analyses, the level of each residual processing agent is evaluated against the CLwc with the following potential outcomes:
4. Determine Compound Specific Cleaning Limit
The manufacturer should follow ISO 10993-17 to set the cleaning limits for each processing agent above the CLwc. When limited toxicological data is available, at a minimum the LD50 values (readily obtained from the MSDS) can be used to calculate the compound specific cleaning limit.
The compound specific cleaning limit will likely be higher than the CLwc. If the level of the residual processing agent observed from the analytical analyses is below the compound specific cleaning limit, the device would be considered clean from residual for the processing agent. If the level of the residual processing agent is above the compound specific cleaning limit, the device would not be clean from that processing agent.
Manufacturers of medical devices are required to demonstrate that their medical devices do not present a threat to patient health from residual processing agents. An experimental strategy was presented that allows the manufacturer to test for all of the potential residual processing agents on the medical device based upon the determination of a worst case scenario cleaning limit. For medical devices where there is a risk of a large number of residual processing agents, the manufacturer may find this approach to be more efficient and less costly than determining the cleaning limit for each compound from a toxicological assessment.
Pine Lake Laboratories is fortunate to have Dr. Michael Ruberto as a retained consult available to support all extractable and leachable studies.
Dr. Ruberto is the President of Material Needs Consulting, LLC which provides consulting services to manage the development and commercialization of medical devices and packaging, with a special emphasis on material selection, extractables and leachables, and supply chain management. He has been an active member of various pharmaceutical working groups that have developed “best practices” for characterizing and evaluating the safety of container closure systems and packaging for several different drug dosage forms. Some of these teams include:
Dr. Ruberto was formerly the Head of Regulatory Services for the NAFTA region at Ciba Specialty Chemicals where he was responsible for worldwide notifications of new products, food contact notifications, and regulatory compliance of Ciba chemicals. At Ciba Dr. Ruberto also served as the Director of Analytical Research. Dr. Ruberto was employed by Ciba for fifteen years.
Dr. Ruberto received a B.S. with thesis from Stevens Institute of Technology and a Ph.D. in Analytical Chemistry from Seton Hall University.
To learn more about Dr. Ruberto, please visit www.materialneedsconsulting.com