Pharmaceutical drug manufacturing and development companies deal with many of the same extractables and leachables (E&L) challenges. E&L risk assessment is a key step in the pharmaceutical drug development process, and yet the current guidelines for E&L are general and do not outline the exact criteria for every situation or form of manufacturing, packaging, and delivery systems.
Importantly, understanding how to choose a lab partner for extractables and leachables and stability testing can prevent prolonged and costly studies, and delays in drug approvals. Guidance on common problems drug manufacturers face during production and packaging can result in cost-effective solutions for required studies including calculating safety thresholds, customizable container closure design assessment, ID of potential contaminants, elimination of unnecessary steps in the process, and handling deficiency responses.
Extractables And Leachables Supply Chain Complexities
Supply chain complexities, such as visibility and data validation, as well as differences in the manufacturing platform, can lead to high costs and turnaround times. As well, delays can be caused by unguided or unnecessary toxicology testing, or poor resource allocation due to inexperience or “canned” protocols from E&L assessment labs.
Geography is another challenge in the E&L validation process, as the global drug development enterprise suffers from a lack of data availability, supply chain visibility across countries, and packaging suppliers. This can result in significant delays before the demand signal reaches drug substance manufacturing and packaging facilities, impacting delivery of the finished product to consumers.
E&L Container Closure Requirements
The requirements for pharmaceutical packaging containers have changed during the past twenty years, and the path to understanding when extractables and leachables data should be submitted to regulators is multi-faceted depending on the type of product, type and use of packaging materials, and the materials involved in manufacturing process as well as the process, itself.
Companies must establish safety and consistency in their primary and secondary packaging by providing chemical composition for every material used in the manufacturing process of a pharmaceutical drug manufacturing packaging component.1
Standard definitions for E&L are set by the USP chapters <1663> and <1664>, with additional information pertaining to packaging materials in <661.1>, <661.2>, and the <665>. Extractables are defined as “organic and inorganic chemicals released from packaging material or delivery systems using extraction solvents under laboratory conditions.”2 Leachables are “chemicals present in the drug product that are from their contact with packaging materials or during manufacturing process under recommended storage conditions or in the accelerated stability program.”2
E&L testing is performed on both packaging containers (glass vials, plastic bags, etc.), and delivery or medical device components (needles, catheters, syringes, caps, seals, stoppers etc.), as well as processing equipment (reaction vessels, tubes, filters, chromatography columns, etc.). Small amounts of chemicals may transfer from any or all of these into the pharmaceutical drug, representing a safety concern for patients. As well, biologics manufacturers face unique E&L challenges as compared to large molecule drugs due to the nature of single use systems (SUS). Since biologics are manufactured and extracted from living biological systems, they are inherently less stable and susceptible to chemical contamination from their prefilled syringes and packaging materials, making it necessary to ensure stability and process quality in scale-up of biologics.
The goal for E&L testing is to design, test, document, and assess the presence of toxic compounds that are above the safety standard, for products taken the orally route, and testing injectables and filling lines against FDA requirements.
E&L Challenges That Affect Cost and Turnaround Times
Many companies face the challenge of balancing cost, turnaround time, and manufacturing requirements in terms of what is necessary to provide to regulators regarding the best toxicology data that can affect patient safety. When choosing a contract research organization (CRO) or analytical lab for extractables and leachables studies, it is important to work with an organization experienced in assessment of analytical evaluation threshold (AET) levels. The following are common challenges and considerations when choosing an analytical partner.
Considering E&L Studies Too Late In The Game
The Challenge: Biopharmaceutical product packaging and container systems must be considered early on in the process of developing a drug. Manufacturing process and equipment impacts the full spectrum. Delayed or limited access to Phase I and Phase II clinical trial data pertaining to dosing components can in turn delay FDA submission of required E&L data for review, resulting in high costs and further delays in getting drugs to market.
The Solution: Removing redundancies in drug development and manufacturing processes can result in the largest cost savings for E&L customers. Beginning with the end in mind is a best practice, and considering the risks is best accomplished by partnering with an experienced lab and experienced toxicologists that have a strong background in chemistry and can streamline analyses and reduce cycle times.
Establishing cost-effective, validated and FDA-approved analytical methods, sampling procedures, cleaning processes, and working with an experienced lab with QC tested and developed detailed extractable and leachable study protocols can mitigate delays.
Efficient Handling of Deficiency Responses
The Challenge: Deficiency responses have become very complex, where the safety threshold calculated for a given drug product container is different from what the FDA thinks companies should use. This disconnect prolongs data collection and validation to remove deficiency responses. A common deficiency in drug approval applications is failure to comply with FDA’s current good manufacturing practice (cGMPs) regulations.
According to the FDA, one of the key challenges in the pharmaceutical products approval process is the unusually high occurrence of product recall and defect reporting data “attributed to inherent defects in product and process design; these data further indicate failures in the implementation of manufacturing process scale-up as well as routine production.”3
The Solution: Specialized expertise and experience are important to proactively convey all aspect of risks and properly address the agency’s query with comprehensive scientific and technical presentation of the data.
The reasons for the many rounds of questions and review cycles, which lead to delays and cost overruns, are due to delayed approval from the beginning, where the FDA is “not satisfied or convinced with the justification given by said Company.”5 In other words, it is critical to swiftly and completely provide complete response (CR) letters in deficiency responses from the FDA.
Recommendations on how to mitigate risk are related to the protocols used to characterize packaging materials and evaluation of ingredients as potential extractables and leachables. An experienced lab will proactively understand and consider the worst-case scenario for those extractables that could become leachables in order to test against them.
Many labs do not have this capability based on their one-size-fits-all extractable and leachable study protocols. In fact, there is no “one-size-fits-all” process for every test because there are so many variables. Getting through this process in an expedient way can require hand-holding between pharma company and E&L lab in the deficiency response process. This deep experience with product and process design to identify failures in the implementation of manufacturing scale-up and routine production can result in cost and time savings before seeking FDA approval.
Chemical Characterization and Narrowing Down Toxic Compound Protocols
The Challenge: Toxicologists working on chemical characterization for E&L can only work with the analytical information they are provided. During toxicology testing, as the number of detected compounds increases, so does the number of potentially toxic compounds. Based on the dosage form, whether injectable or oral suspension, customers need to know the safety threshold and composition of the drug product in that container closure to test for common problems, such as total petroleum hydrocarbons (TPH). Missed libraries of toxins can result in unnecessary protocols.
The Solution: Optimizing this process can be done by partnering with a lab that has a comprehensive library of toxins/leachants. In the process of chemical characterization and identification of leachants, two E&L testing techniques have typically been performed, including gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS). A big differentiator in the length and cost of the E&L study are custom leachant libraries. Labs with custom libraries can help with identification of leachable compounds and toxicity from plastic in drug product, for example. Importantly, before a company can determine toxicity, they first need to identify the toxin.
Understanding Susceptible Drug Formats And Container Complexity
The Challenge: Any container-closure system or other packaging that interacts with a drug must be studied as it is considered part of the drug product and is subject to regulatory approval. Certain drug formats, including inhalation aerosols and injectable suspensions, have a lower safety threshold than oral drugs due to the bypassing of the GI system and first pass metabolism. Inhaled, ophthalmic, and injected drugs leave patients more vulnerable to impurities from packaging and manufacturing components.
Where the complexity of design of a drug container is high, experience and a custom approach for the specific type of product and plastic is important. Overcoming challenges related to the specific drug format or the manufacturing and packaging materials used to create a particular pharmaceutical product can have critical impact on the drug approval outcome.
The Solution: Pharma companies may need to take extra precautions to prevent contamination. In protocol design, there can be a lot of trial and error for complex containers. A lab that has a large number of pre-existing protocols for organic and inorganic leachants could reduce this trial and error downtime.
Pharmaceutical companies must outline their cleaning mechanisms, including chemistry for contaminant removal, with multi-step documentation to obtain a final, clean validation report for the FDA. The FDA inspection is a critical final step, and if deficiencies are found, the consequences could include drug recall and shut-down of the operation. The inspection report and the protocols used to reach compliance are critical, and selection of an E&L lab should include forethought of the experience level and track record with cleaning verification and validation.
Considerations For Single-Use Systems (SUS)
The Challenge: In the past, biopharmaceutical drug manufacturing facilities commonly used stainless steel equipment, and leachants weren’t a significant concern. Now, facilities often rely on single-use equipment, which is disposed of after use rather than cleaned. In particular, SUS is used in the manufacture of biologics.
These single-use systems are typically made from multiple materials and exposed to gamma radiation that can create trace-level leachables. In many cases, unique solvents and process conditions require custom analytical techniques to detect the widest possible range of chemical compounds.4
Due to the complexities of single use systems, regulatory bodies require more E&L data for this equipment than they do for stainless steel components. At the same time, there is a lack of standardization for specific SUS testing methods for extractables in the biologics market. Companies have had to generate SUS extractables through extrapolation and interpretation of existing regulatory requirements for large molecule drugs.4 There is large room for error, and adequate risk-assessment can be cost- and time-consuming.
The Solution: Single use component, oral or liquid suspension, and solid dose compliance are not difficult issues to resolve; typically testing is not too extensive as biologics are generally in glass bottles or blister packaging.
For non-SUS container closure systems, the regulatory requirements are based on toxicological evaluation of the safety of extractables. The documentation takes into account the “specific container closure system, drug product formulation, dosage form, route of administration, and dose regimen (chronic or short-term dosing).”1
The lucrative biologics market uses single use disposable manufacturing equipment. Biologics companies started using disposable equipment where a leachant could end up in the product in those SUS lines making it critical to do leachables testing for sterile manufacturing products for injectables. This is where customization is a key differentiator. There may be 8-10 components in a given manufacturing line that need to be tested. An experienced lab will be familiar with combinations of similar plastics and components in test lines and will take a risk-based approach based on the application, point and phase of use in confirming safety and efficacy for the product. Responsive consulting can be beneficial in these cases to expedite assessment with predetermined E&L testing protocols.4
Using Validated Test Methods
The Challenge: Ensuring the right safety thresholds requires extractable and leachable study protocol development. During the extractable study, chemists must identify and quantify all chemicals that might be extracted from manufacturing or packaging components under exaggerated conditions. This testing can be used to develop deep analytical methods for leachable studies, designed to detect the chemicals that could migrate into a drug product over its shelf-life, under conditions of normal use. These leachable studies can be considered a subset of extraction studies. For an inexperienced lab, creating and validating E&L studies from scratch can be expensive and/or redundant.
The Solution: If the right protocols are not performed, companies can miss potential risks, adding costs or redundancies. This makes taking a canned approach to drug development detrimental.
Another aspect is E&L scope, and approach. Ideally, a lab will take a risk-based approach, meaning that if the customer is not validating test methods because the FDA has not required them, an experienced lab is knowledgeable about the approval process and can inform clients about a risk associated with a given method. It is also important to understand whether or not, if the findings are below the safety threshold, the customer can come back to the lab for further testing without added costs.
Many companies have “canned” test protocols; if a customer’s need fits that lab’s protocol, especially in the filling line, they can do the work without issue. Or, a lab may have an elaborate approach, but the added tests are ultimately not value-added to the final result. Look for a lab that can tell customers up front about potential extra steps, and can then eliminate unnecessary steps in the process.
The Critical Step: Selecting An Analytical Partner
Many common E&L challenges pharmaceutical drug manufacturing and development companies face during production and packaging are really about finding timely and cost-effective solutions for regulatory approval. A critical step in analyzing extractables and leachables is the selection of a research lab partner early on in the process that understands the process, is familiar with testing techniques and manufacturing, and can tailor extractable and leachable study protocols for each unique biopharmaceutical. Avomeen is a full-service independent laboratory in good standing with FDA regulatory guidelines. We work with customers to effectively incorporate a risk-based approach to extractables & leachables studies with the assistance of consultative expert scientists who are well versed in FDA regulatory requirements, advanced analytical technology, and interpretation of data. Learn more about Avomeen’s E&L expertise for the pharmaceutical and life sciences industries, or contact us to request a customized proposal.
- U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (1999, May). Container Closure Systems for Packaging Human Drugs and Biologics. Retrieved from
- Zhong, M. (2018). Extractable and Leachable Testing in Pharmaceutical Analysis. Pharm Anal Acta 2018, Vol 9(6): e193. DOI: 10.4172/2153-2435.1000e193
- The Food and Drug Administration (FDA) Office of Pharmaceutical Quality (2018). FDA Pharmaceutical Quality Oversight. Retrieved from https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf
- Ding, W., Madsen, G., Mahajan, E., O’Connor, S., and Wong, K. (2014). Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing. Pharmaceutical Engineering 2014, Nov/Dec, Vol. 34, No. 6.
- Tripathy, Swagat & Pn, Murthy. (2018). IMPORTANCE OF DEFICIENCY RESPONSE IN PHARMACEUTICAL ENVIRONMENT FOR DRUG APPROVAL. International Journal of Drug Regulatory Affairs. 2. 14-18. 10.22270/ijdra.v2i4.148.