Susan Haigney

spoke with Amy Lavelle, associate director, Bioanalytical Lab, PPD Clinical Research, Thermo Fisher Scientific, about the challenges of performing bioanalytical studies and how contract research organizations (CROs) can help mitigate possible regulatory submission problems.

 What are the challenges in performing bioanalytical studies?

Common challenges include supply chain issues and the availability of proper quality reagents. As science continues to find new modalities for therapeutics, complex molecular structures and delivery systems pose challenges for the development of specific and robust assays. For example, in the cell and gene therapy space, use of adeno-associated virus (AAV) vectors for drug delivery creates complications for immunogenicity assessment due to the fact that pre-existing antibodies to the viral vector make finding negative controls and appropriate cut points difficult. When evaluating low-level biomarkers, highly sensitive assays are required, as the assay range needs to be relative to expected biological concentrations, which requires appropriate reagents and equipment.

: What are some mistakes companies make in performing bioanalytical studies and/or a bioanalytical study program?

 The best way to avoid mistakes is to fully understand regulatory requirements and the appropriate guidance to follow when performing bioanalytical studies. It’s also important to allow sufficient time for the laboratory to develop a robust and validated method intended for sample analysis at the clinical stage. The type of lab compliance and assay validation parameters are key factors in ensuring the data are fully supported for the appropriate regulatory submission. Utilizing a CRO that is experienced with and knowledgeable of agency requirements will help prevent the sponsor from facing any submission issues.

 What kind of data from bioanalytical studies are included in regulatory filings?

This is dependent on the drug and its mechanism of action, the proposed indication, and the phase of the trial. Additionally, it depends upon the history of the data already available on the drug and similar compounds or if the need for the drug allows for alternatives, as is the case with orphan status.

An investigational new drug (IND) filing application to start human clinical trials is used to determine if the proposed drug is reasonably safe to administer to humans. Regulatory agencies will review preclinical data, such as pharmacology and toxicology information, genotoxicity, drug absorption and metabolism, and toxicity of metabolites. The proposed clinical protocol for the trial as well as manufacturing information for the drug is discussed.

Phase I, II, and III clinical trials are performed based on FDA-approved protocols. In order to manufacture and sell the drug, clinical test data and analysis from Phase I–III are used in a new drug application (NDA) to determine if the drug is safe and effective for its context of use and if there are any risks associated with the drug, and if so, that the benefits outweigh any risks.An abbreviated new drug application (ANDA) also may be filed for generic drugs. These data must demonstrate bioequivalency to the original drug.

How are these data compiled and presented to regulators? Is the process different for FDA versus the European Medicines Agency (EMA)?

 For an FDA IND filing, data from animal and in-vitro toxicology and pharmacology studies are compiled with drug manufacturing information and clinical protocols proposed. In addition, available clinical testing or data from foreign countries may be included. A pre-IND meeting with FDA may be conducted to ensure compliance moving forward.

Animal pharmacology/toxicology information includes a summary on pharmacology and drug disposition,pharmacokinetic (PK) bioanalytical data, and mechanism of action (MOA) of the drug; a toxicology summary, including toxicology study design, findings, and data from toxicology and toxicokinetic studies; a full toxicology data tabulation; and toxicology GLP [good laboratory practice] certification.

For an FDA NDA filing, clinical data from human studies (Phase I–III), which include safety and efficacy results, are compiled and also include drug product control, manufacturing, and stability data. For an ANDA, bioequivalence results also are required.

While the United States has one main body governing drug approval, Europe has multiple agencies, including the EMA, the Committee for Medicinal Products for Human Use (CHMP), and various national health agencies. There are also multiple registration processes in Europe, including centralized, decentralized, mutual recognition, and national. There is a two-step process similar to the US, which includes the clinical trial application, approved at the member state level, and the marketing authorization application, which is approved at the member state and/or centralized level.

Are data from bioanalytical studies a factor in post-marketing of approved drugs?

Yes, post-marketing studies are often important for optimizing the drug’s use. For instance, drug-drug interactions, dose response, or safety studies and mortality/morbidity studies. Other post-marketing studies may be requirements set by FDA (post-marketing commitments) to further monitor and characterize the drug’s effects and safety, such as in subpopulations.

 What are the benefits of outsourcing bioanalytical studies?

 The benefits depend on the needs and resources of the sponsor. These benefits can include, but are not limited to, laboratory resources including technology, expertise, and experience; regulatory knowledge; end-to-end support from trial design to analysis to regulatory submission; dedicated support groups such as quality control, quality assurance, data management, report writing, and statistical analysis; and time/cost savings. Outsourcing frees up internal resources for alternative needs and enables sponsors to work with limited dedicated internal personnel. Capacity and capabilities are often drivers for outsourcing.

 How can sponsor companies and CROs work together to gather and present these data to regulators?

CROs can work with sponsors to ensure appropriate regulatory guidance and testing are being followed for data submission, as well as to help to ensure data and reports are compiled in an appropriate format for submission. CRO labs are subject to audits by FDA, and they often have experience in their interactions with regulatory agencies that can benefit the sponsor. Some CROs have regulatory compliance staff to work with the sponsor as they design and execute their trials.


Volume 46, Number 9
September 2022
Pages: 54–56

When referring to this article, please cite it as S. Haigney, “Robust Bioanalytical Studies Can Aid in Regulatory Submissions,” 

Articles

It is important to understand regulatory requirements and study challenges to develop and validate the appropriate methods for a bioanalytical study program at the clinical stage.

Robust Bioanalytical Studies Can Aid in Regulatory Submissions

 spoke with Andrew Anderson, Global Head Strategic Account Managementand Mary Todas, Director Technical Development and Regulatory Affairs, both with Pfizer CentreOne, about best practices for API quality.

PharmTech: How crucial is it for pharma manufacturers to ensure the safety of APIs? What are the possible repercussions of low-quality and/or ineffective APIs?

 Much of the world’s supply of pharmaceuticals depends on this critical aspect of the drug product supply chain, and manufacturers around the world shoulder a tremendous responsibility to assure the quantity, quality, and continuity of supply. Unfortunately, the world has seen the impact of quality-compromised API supply chains, resulting in injury and death, the worst possible of all patient outcomes.

PharmTech: What are the steps an API manufacturer must take to ensure quality throughout the development and manufacture of an API?

The first step in any supplier acquisition journey begins with a thorough review of the batch release specifications to determine if a given supplier can actually meet customer needs. Soon after, a comprehensive audit should be conducted which is the basic means to determining its status as a quality supplier. What is their cGMP [current good manufacturing practice] status? Those two steps are just [the] beginning of the scrutiny and qualification which have to be ongoing over the life of the contract to make sure that quality is sustained.

PharmTech: What are the steps sponsors should take to ensure the quality of APIs sourced from a supplier used in final products?

Sponsors do have a responsibility as well because they too are obligated to assure the quality of their products, regardless of who manufactures their API. All of this boils down to cGMP compliance, not just quality of manufacturing, but the quality systems as well. It is imperative that quality systems are robust, risk-based, and error free. Effective API supply collaboration requires transparency and trust, but that trust must be verified, established from the very first meeting.

PharmTech: International Council for Harmonisation’s Q7A GMPs for APIs touches on all aspects of API production from facilities to equipment to materials management. Of all the areas the guidance covers, is there one particular aspect of API manufacturing that is more crucial for ensuring API quality? 

 No. Of course not. CGMP dictates mastery of all aspects of control and quality relative to API manufacture. There is no parsing it, and quality compliance depends on the careful assessment of risk, and the manufacturer’s response to it procedurally and operationally. Your API supplier’s abilities in this regard should be revealed in the audit. If you have a robust relationship with your supplier, you will know where their weak points are, if any, and where you need to concentrate your audit.

PharmTech: What methods are available for testing the effectiveness and safety of APIs?

Compliance to compound monographs is an established starting point but process analytical controls and processes developed using quality-by-design principles are building in effectiveness and safety into API manufacture, as well as batch consistency from year after year and campaign to campaign.

Pharmaceutical Technology spoke with Andrew Anderson, Global Head Strategic Account Management and Mary Todas, Director Technical Development and Regulatory Affairs, both with Pfizer CentreOne, about best practices for API quality. 

Industry Perspectives on Quality–A Conversation with Pfizer CentreOne

 spoke with Niamh Lynch, Executive Director, Global Head of Quality, Lonza Small Molecules, Basel about best practices for API quality and the impact of the nitrosamine contamination situation.

 How crucial is it for pharma manufacturers to ensure the safety of APIs? What are the possible repercussions of low-quality and/or ineffective APIs?

 What is really important for API manufacturing is to ensure that the specifications are appropriately set, especially for any impurities that might be toxic in nature. The repercussions can be huge, with the worst being patient impact—either because the drug is not doing what it should, or is doing something that it shouldn’t, reputational damage for the company, and access to the markets where medicine is needed.

 What are the steps an API manufacturer must take to ensure quality throughout the development and manufacture of an API?

 It is essential that all possible impurities are defined during development, and toxicological assessments are performed. Of particular importance are any genotoxic impurities. These will need to be controlled or eliminated throughout the processing of the API, so that the product meets all the required specifications.

What are the steps sponsors should take to ensure the quality of APIs sourced from a supplier used in final products?

 It is important that the sponsor chooses the right outsourcing partner. It should be one who has a mature quality set-up, with a good quality mindset, and a willingness to continue to move with the regulatory trends. It is more important to get it right and manage changes than purely look at cost: if a problem is found further down the line, the costs will be far higher.

 The International Council for Harmonisation’s Q7A GMPs forAPIs touches on all aspects of API production from facilities to equipment to materials management. Of all the areas the guidance covers, is there one particular aspect of API manufacturing that is more crucial for ensuring API quality?

 One area where we commonly find quality issues is with incoming materials. This might be solvents, raw materials, or even processing aids. Another big concern is when changes are made to chemical processes without adequate checking. Whether this is a shift to a new raw material supplier, a change of solvent, or even the use of different equipment, if the effects of the changes are not assessed appropriately, this can cause huge problems, particularly with the formation of additional, unexpected impurities.

 What methods are available for testing the effectiveness and safety of APIs?

 Many different methods are available, but LC-MS [liquid chromatography-mass spectrometry] and GC-MS [gas chromatography-MS] are particularly important.

 What has the industry learned from the nitrosamine contamination problems in blood pressure medications?

 The industry has learnt that, even though a supplier can state that it has performed an assessment against the regulatory requirements, it is extremely important that the manufacturing authorization holder performs not only a paper assessment, but analytics in addition. It also became apparent that if a change is made to a process, whether to solvents, catalysts, or a new supplier of starting materials, it can result in the formation of additional impurities.

 Have regulators and industry resolved the nitrosamine problem, or is it continuing? What steps can be taken to ensure a similar situation does not occur in the future?

The regulators reacted very rapidly to this issue, which started back in 2018. They were quickly on board, assessing the products in question and the suppliers manufacturing them, as well as identifying further nitrosamines that were being formed. They also set appropriate specifications for industry to follow. Industry has also reacted appropriately, implementing the necessary assessments and analytical methods. To ensure we do not have similar situations in the future, it is important that the drug developer also performs appropriate assessments during development, and the drug manufacturer assesses changes appropriately during the lifecycle of the product.

 Are there other broadly used API groups that might cause a similar problem to nitrosamines? Are there other types of testing that can avoid this kind of situation with other APIs?

 How nitrosamines are formed is well known, and well documented. All manufacturers, therefore, need to perform an assessment of all of their products. LC-MS and GC-MS are the key techniques that should be used to identify the presence of any nitrosamines in the products.

Pharmaceutical Technology spoke with Niamh Lynch, Executive Director, Global Head of Quality, Lonza Small Molecules, Basel about best practices for API quality and the impact of the nitrosamine contamination situation.

Industry Perspective on API Quality–A Conversation with Niamh Lynch of Lonza Small Molecules

Effective and safe APIs provide the necessary element of drugs to treat patients with a variety of health conditions. It is, therefore, crucial that the quality of APIs, along with other ingredients that make up a medicine, is of primary importance to drug developers and manufacturers.

spoke with the US Pharmacopeia (USP) and the European Directorate for the Quality of Medicines & Healthcare (EDQM) to gain their perspectives on API quality. 


To read the full interviews, click on the links below:

Ensuring API Quality—The EDQM Perspective

spoke with representatives from the European Directorate for the Quality of Medicines & Healthcare (EDQM) about API quality from their perspective.

Ensuring API Quality—A Pharmacopeia Perspective

spoke with Ed Gump, VP Small Molecules at the US Pharmacopeia (USP) about API quality from the standards perspective.

“It is the API, that attributes the efficacy of a drug,” says Aloka Srinivasan, principal and managing partner at RAAHA LLC. “In other words, a drug is a drug because of the API, otherwise it is just a placebo. Thus, it is of utmost importance that the pharmaceutical manufacturers assure the safety of the API.”

According to Meera Khullar, senior vice president of Quality and Compliance, Curia Global, API quality is an essential requirement. “Current regulations worldwide provide zero flexibility when it comes to the quality of APIs released from [manufacturing] sites and reaching the market,” Khullar states. “Without global standards of quality, production of much-needed treatments can be derailed just when patients need them the most.”

“The clue is in the name; the API has an ‘active’ impact on the patient. The pharma manufacturer is ultimately responsible for the safety of the drug product and therewith of the API. In the worst case, an unsafe API can do harm to a patient, which can result in recalls, damage to reputation, financial loss, and potentially punitive actions by regulatory agencies,” warns Siegfried Schmitt, vice president, Technical at Parexel.

So how do API manufacturers and sponsor companies ensure the quality of their product? It’s all about assessing risk. Performing robust risk assessments of the manufacturing process is crucial.

“Robust risk assessments help manufacturers understand their processes, including degradation pathways and impurity formation, and optimize them to meet quality targets. In this way, manufacturers can ensure quality by design—developing a process that detects and minimizes impurities and guarantees quality,” says Ankur Deshpande, director, Process Development Quality at BIOVECTRA.

“One of the key considerations for API and resulting [drug product] safety is assessing potential impurities that may be introduced from the interaction of the manufacturing process stream to manufacturing component materials (e.g., filter membranes, polymeric or elastomeric tubing, polymeric storage vessels and closures, etc.),” says Xiaochun Yu, senior principal scientist, PPD. “The approach for evaluating and controlling this risk is well described in United States Pharmacopeia <1665>.”

A quality system that employs good manufacturing practices (GMPs) is also necessary, adds Schmitt, and the personnel involved in the quality system are key. “A system is only as good as the persons who apply it and adhere to it. Thus, having suitably trained and qualified staff and of course, also suitably designed and equipped facilities are a prerequisite. It sounds simple and logical, but it requires a quality mindset to implement and follow.”

Documentation is also key, continues Mike Johnson, senior director, Quality, Cambrex High Point. “A sponsor might develop an API that is a miracle to the patient, but if the quality system has not been properly built or continuously managed, missing parts or inaccuracies within the development package may arise. This can cause delays in approvals and rework, as auditors and regulatory reviewers may question the quality and validity of the API being developed,” he says.

A crucial area in API quality is cleaning with contamination controls, specifies Johnson. He also points to facility design, equipment, and personnel training as part of a robust cleaning program. “When an API is produced in a reactor or isolated for final pack out, we must confirm that only the one API is present and there are no concerns for contamination from other materials,” says Johnson.

For more from industry experts about API quality, read the interviews below:

Industry Perspective on API Quality–A Conversation with Niamh Lynch of Lonza

. Performing testing on APIs, whether produced in house or obtained from a supplier, is essential to establishing the quality of the API used in the finished drug product. High-performance liquid chromatography (HPLC) is a key testing method for ensuring API purity, asserts Johnson, and it is a common and critical testing method. Mass spectrometry (MS) and gas chromatography (GC) are also effective testing methods, but numerous methods should be used to meet regulatory guidelines, stresses Johnson. “A series of different methods and analytical techniques must be used to ensure a full battery of tests is performed to support that the API is effective and safe for patients,” he says.

Other testing methods include charged aerosol detectors and multi-angle light scattering (MALS) detectors, according to Peter Phillips, vice president of Quality at BIOVECTRA. “But the use of these methods depends on the areas of risk identified by the sponsor through their clinical trials. This information drives the manufacturer towards the appropriate technology to detect and eliminate that risk,” he says.

“Continual advances in the sensitivity, specificity, and accuracy of analytical technologies contribute to increasing confidence in the ability of API manufacturers to ensure the quality of final API products,” says James Lawler, general managerat C2 PHARMA. “For small-molecule APIs, common techniques include Raman, ultraviolet, infrared, and UV spectroscopy; HPLC; LC–MS; LC–tandem MS (MS/MS); GC; GC–MS and GC–MS/MS; and particle analysis, among others. These methods are used during product and process development and for final API release. GMP drug substance release testing requirements are extensive and include testing materials against specification for identity, purity, the level of impurities, certain physical properties, among other attributes. The specific requirements depend on the modality.”

 Sponsor companies often source APIs from third-party suppliers. Sourcing of these materials often requires a commitment to quality above costs to ensure that the final product is effective and safe.

The selection of low-quality APIs to reduce manufacturing costs can put the whole supply chain at risk, notes Lawler. “The lowest commonly acceptable quality API manufacturer typically put everyone else out of business for that API while also being the one with the highest risk of failure. Once they fail, like a domino effect, they wipe out the whole supply chain leading into shortages which are extremely detrimental to patient health,” says Lawler.

Raw material selection is an important aspect of API quality, especially combined with robust process validation, according to Adriana Malizia, director of Quality, Aceto. “Raw material selection and qualification involve the evaluation of the supplier QMS [quality management system] and lay the foundation for the processing of the material to manufacture the API,” says Malizia. “This is further supported by a thorough validation of the manufacturing process which should identify critical process parameters that will act as the control mechanisms to establishing consistent process and product quality.”

A holistic approach to qualifying suppliers is also key, emphasizes Khullar. This approach should consider the quality aspects of the supplier at the beginning of the relationship and include the supplier’s technical capabilities, equipment, technology, and personnel. “The assessment also should evaluate a supplier’s track record of reliability for producing consistent products in line with emerging requirements, including its history of regulatory compliance. Furthermore, it should address whether the supplier’s ongoing quality performance is in line with the sponsor’s standards across the supply chain. Sponsors should gauge and confirm an environment and culture of continuous improvement. Ultimately, the strongest sponsor and supplier partnerships require alignment between each organization’s quality systems,” says Khullar.

Site audits of API suppliers must be performed as part of a sourcing program, asserts Johnson. “Keep in mind that audits are a snapshot in time, so it’s important to incorporate additional technical and business oversight throughout the relationship. Sponsors can ensure a second confirmation of quality checks at periodic timepoints through a use test in the production environment, followed by quality control testing,” Johnson says.

Suppliers should have a robust quality system to detect and correct problems with their product, confirms Phillips, and API manufacturers should have the technical background and expertise to plan for problems. “It is essential that manufacturers can walk sponsors through the technical process, both from a manufacturing and an analytical perspective,” says Phillips.

An additional consideration for sourcing of APIs is ensuring critical quality attributes (CQAs) of the API. “For example, shipping an ingredient at the wrong temperature can cause issues severely impacting quality. Depending on the particular product and its unique [CQAs], some factors might be more important than others, but it is always case-dependent, and there are always multiple areas that can impact API quality,” says Phillips.

Sponsors should request information from the API supplier related to the drug master file, asserts Srinivasan. “The sponsors should make sure that the API was adequately characterized, the impurities were identified, and their limits justified. The controls for the API should be adequate,” she says. “In addition to impurities, one should make sure that assay, polymorphic forms, particle size, and water content are adequately controlled. The sponsors should also make sure that the analytical methods used by the API manufacturer are suitable for the purpose and robust.”

An example of what can go wrong with APIs when impurities are present is the nitrosamine contamination in sartan drugs (1). Individuals are exposed to nitrosamines, which are common in water and foods, to some level in their environment. However, these impurities may increase the risk of developing cancer in some people, according to FDA, and in 2020, industry began issuing recalls of drug products contaminated with nitrosamines (2).

“The nitrosamine saga is ongoing, and industry is learning new things every day related to nitrosamines,” says Srinivasan. “Currently, the agencies have moved beyond low molecular weight nitrosamines, which arise from reagents and solvents to larger API like nitrosamines, which FDA has termed as NDSRIs (nitroso drug substance related impurities). These nitrosamines are formed when the API itself is an amine (secondary, tertiary, or quaternary) and is capable of forming a nitrosamine in presence of a nitrosating agent like nitrite, which are ubiquitous. This has made the industry aware that they need to make sure that the water or the reagents they use are nitrite free. It has also made the industry more careful regarding the cleaning of shared equipment to avoid any contamination with a nitrosating agent. Industry is rethinking the route of synthesis for many APIs, including “sartans” to see if nitrosating agents can be avoided. Last but not least, industry has started paying serious attention the quality of recycled solvents, which could be a player in the formation of nitrosamines.”

The presence of impurities may not be obvious, according to Duu-Gong Wu, Regulatory Affairs, PPD, especially when an interaction with non-toxic excipients results in impurities in the API. With the nitrosamine contamination in sartan medications, the manufacturing process itself was the culprit and dimethylformamide combined with sodium nitrite in the presence of an acid led to the formation of N-nitrosamines.

According to Lawler, the N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) contamination in these drugs occurred because recycled solvents were used to reduce costs, and formulations of some APIs with specific excipients resulted in nitrosamine formation. “When the problem first arose (due to poorly considered process changes), awareness of the need for better risk analysis of the synthetic routes used to manufacture APIs with respect to the potential for production of both known and unknown impurities and how to prevent/control them increased substantially across the industry. The importance of effective process-change control processes and the need for careful oversight of API suppliers was also highlighted,” Lawler says. “Furthermore, the critical need for scientific competence and the negative impact that continuous cost-cutting measures can have on quality was clearly demonstrated from the nitrosamine crisis.”

The nitrosamine situation stressed the importance of a robust process validation, which can identify by-products and/or impurities created during manufacturing, explains Malizia. “The nitrosamine contamination … has underscored the importance of these initial process analyses and risk assessments which should be supported by analytical testing where doubt exists. It further demonstrated that the collaboration of raw material and excipient suppliers in identifying potential risk factors is necessary for early detection and ultimately patient safety,” says Malizia.

Because contaminates can be introduced early in the manufacturing process, which can then impact the entire process, the need for “strict control” over the pharmaceutical supply chain was also emphasized by the nitrosamine situation, emphasizes Deshpande.

Srinivasan believes the scope of the nitrosamines problem has expanded from small nitrosamines created from reagents and solvents to NDSRIs, and the problem may take years to resolve. “Considering that more than 40% of drugs approved by agencies all over the world are secondary and tertiary amines, there are potentially hundreds or thousands of drugs that need to be evaluated for these larger nitrosamines, which have very little to no data in the public domain. Agencies have recommended limits which in most cases are unachievable based on currently available analytical capabilities,” she says. “The API industry should take a holistic look into the route of synthesis of an API and the reagents, solvents used to make sure that they are not missing anything related to mutagenic impurities. The other aspect, which cannot be stressed enough, is the need to follow appropriate GMP during API manufacturing and avoid contamination.”

The nitrosamines situation has shown that an analytical assessment of the manufacturing process, in addition to a paper assessment, is essential, according to Niamh Lynch, Executive Director, Global Head of Quality, Lonza Small Molecules, Basel. “It also became apparent that if a change is made to a process, whether to solvents, catalysts, or a new supplier of starting materials, it can result in the formation of additional impurities,” Lynch says.

 Industry and regulatory bodies jumped quickly to tackle the nitrosamine problem. Regulators across the globe have collaborated to assess the risk and develop recommendations, according to Khullar. “For example, the US guidance [issued by FDA] goes beyond products of known concern and applies to all chemically synthesized APIs and drug products containing chemically synthesized APIs.Recommendations for both API and drug product manufacturers cover approved and marketed drugs as well as those in development. This is an ongoing effort, which underscores the need for continuous improvement and the need to adjust to meet evolving standards,” says Khullar.

Regulators are using tools to track potential contamination trends, asserts Phillips, but manufacturers should remain diligent and use risk assessment tools to anticipate potential issues before their products reach patients. “That being said, we are dealing with complex molecules and products, so it can be very difficult to predict everything that can happen. Therefore, it’s important that CDMOs [contract development and manufacturing organizations] and pharma manufacturers work hard to foster a culture where quality is highly valued,” says Phillips.

“In general, awareness of the nitrosamine contamination issue is high within the pharmaceutical industry across the entire value chain,” says Lawler. “Collaboration between international regulatory agencies and API and drug product manufacturers continues with respect to identifying any additional sources of nitrosamine impurities not yet uncovered. As more information is obtained, greater understanding and tightening regulations will likely lead to a reduction of such occurrences in the future. Unfortunately, the root cause of the nitrosamine crisis, namely poor scientific knowledge at the API manufacturer and continuous cost cutting programs for APIs is not addressed,” confirms Lawler.

Malizia stresses that while the nitrosamine problem may not be fully resolved, better control strategies have been implemented across the world that may help the industry avoid similar situations. “The fact that risk assessments and testing are being adopted by less regulated suppliers (raw material and excipient manufacturers) demonstrates that there is a better understanding of the importance of fully comprehending a product’s impurity profile and that collaboration across the industry is key in avoiding similar recurrences for other potential contaminants,” Malizia says.

“Manufacturers are under pressure to better understand the nitrosamine problem, and regulators require manufacturers to perform specific assessments for nitrosamines under M7 ICH [International Council for Harmonisation],” concurs Phillips. “There is always the potential of a new nitrosamine-type issue arising, but the agencies and the companies themselves are continuing to monitor processes and products to ensure this does not happen again.”

Quality control at each stage of API manufacturing is crucial to ensure the quality, safety, and effectiveness of drug products. “The compliance of all stages of manufacturing to CGMP also plays a critical role in maintaining the quality and safety of API, especially after the regulatory approval,” says Derek Wood, senior principal scientist, PPD.

“The moment an API leaves our site, we must have full confidence that we have ensured the API is the correct quality and has been fully tested to meet current product specifications. Strong quality oversight ensures the patient can confidently use their medicine without hesitation. Low-quality and ineffective APIs simply break the trust of the patient, and more importantly, could cause harm to them,” concludes Johnson.

1. FDA, Information about Nitrosamine Impurities in Medications, 

2. F. Mirasol, “Pharma Industry Contends with Contamination-based Recalls,” 

Pharm. Technol. Solid Dosage Drug Development and Manufacturing Supplement


Vol. 46, No. 8
August 2022
Pages: 16–19

When referring to this article, please cite it as S. Haigney, “What Goes Wrong When API Quality is Compromised?,” 

The nitrosamines contamination in “sartan” drugs emphasized the importance of risk assessment in the manufacture of active pharmaceutical ingredients.

What Goes Wrong When API Quality is Compromised?

Automation plays a role in several pharmaceutical manufacturing operations, including packaging. Specifically, the automation of processes can save resources, time, and money. Outsourcing the packaging of bio/pharmaceutical products can offer sponsor companies and manufacturers a variety of options from clinical development to commercial production.

 spoke with Patrick Ferguson, managing director at Tjoapack, and Markus Hörburger, product and service manager at Vetter Pharma International GmbH, about the benefits of automating pharmaceutical packaging and the services contract organizations can provide.

 How can automation be used to optimize pharmaceutical packaging?

 Similar to other industries, the main benefit of automation in pharmaceutical packaging is replacing time-consuming manual assembly and packaging steps. Often, automation also has the advantage of being accompanied by digitalization. Digital processes allow for the gathering of various data around the automated packaging that are a significant basis for the identification of further process improvements (for example, predictive maintenance).

 The introduction of automation into pharmaceutical packaging processes has become the industry standard for any packaging company looking to positively impact the bottom line. Investment in automation has a direct and positive impact on quality, efficiency, productivity, and profitability. Additionally, it allows contract packaging organizations, such as Tjoapack, to be more competitive.

How is automation used for the different types of packaging, such as blister packs, prefilled syringes, vials, bottles, etc.?

 In the pharmaceutical packaging industry, equipment providers have continued to develop solutions to tackle nearly any task. Quality and robustness are being designed into the processes from the ground up. Inspections, verifications, integrity, and repeatability are all standard concepts in terms of the overall design of a particular solution.

While the sequence of individual tasks for the packaging of blisters, prefilled syringes, vials, bottles, kits, etc. are often different from one type of SKU to another, they all have many common attributes where automation is being used. Examples include: presence and verification of packaging component, presence and verification of product (bulk and/or semi-finished goods), presence and verification of labeling, documentation of critical attributes, inspection of components, WIP, and finished goods, [and] serialization and aggregation of packaged goods.

 Automation adds the most value when various packaging process steps, such as labeling, assembling, and cartooning, can be processed within a fully automated line. Ideally, different packaging types can be processed on one line. For example, syringes can be automatically assembled in safety devices or autoinjectors respectively. Further down the line, syringes, assembled autoinjectors, or safety devices can then be packed in blisters and folding boxes or in more sustainable paper-based solutions depending on customer requirements.

What goes into formulating effective automation strategies for pharma packaging?

 In my opinion, the formulation of an effective automation strategy starts with an evaluation of the process needed to create the end product. Critical inputs include batch size, annual volume, margin, and the tasks required. Obviously, it doesn’t make sense to invest millions of dollars to fully automate a kitting process that runs only 500 units once a year. The investment into an automated solution must make good financial sense. Once the critical data has been collected and evaluated, a strategy can be developed with multiple automation options included. A cost-benefit analysis should then be developed for each option. Depending on the level of investment, proposals are then routed to the appropriate level with collaboration from multiple departments.

Working with equipment manufacturers and solution providers is another critical part of this process. Choosing the right vendor to partner with can make or break a project. Vendors often have standard solutions that work as is or can be customized to your need. When no solution currently exists, a good partner can take your concept and develop a custom, turn-key solution.

 The development of our packaging strategy starts by considering the needs of the end-user. As a CDMO [contract development and manufacturing organization] in high-quality filling, device assembly, and secondary packaging for injectables, developing an effective automation strategy involves the incorporation of many different assembly and packaging processes. As it pertains specifically to automation, the high complexity of the diverse processes plays a central role in the formulation of a suitable strategy. In addition, the lifecycle status of the products has a major influence on the degree of automation and, therefore, the automation strategy. In early clinical phases when batch sizes are small, highly automated processes can limit flexibility and efficiency. As the product matures, the batch size typically increases. When clinical Phase III is reached or at the launch and associated start of commercial production, highly-automated assembly and packaging processes are preferred.

Which kind of automation services/equipment are available for pharma packaging?

Common automation concepts include equipment that is being used for single-packaging processes; for example, assembly as well as the incorporation of a fully integrated line that combines several pieces of equipment for the entire packaging process. Collaborating robots (cobots) are another concept for the automation of pharma packaging. Through the use of cobots, the interaction between employer and machine is achieved, resulting in increased automation of manual processes. At Vetter, we have been using this collaborative approach for several years and are currently using cobots within our secondary packaging lines for feeding-in alcohol swabs. We have also gained experience in the assembly of piston rods and repacking syringes in trays in stand-alone systems.

Automation comes in a variety of flavors. Many people not familiar with automation think of assembly lines with robots performing all the tasks. Automation in its entirety can range from lights-out operations with virtually no human interaction, to simple line-level, task-specific enhancements to a process. Sensors, gating mechanisms, and other mechanical inputs can easily be added to a line to improve a process and reduce labor and waste. Fully automated solutions can be implemented to perform a full sequence of tasks yielding a quality product with little human intervention. Naturally, the validation of these automated processes is critical.

 Why should manufacturers outsource their packaging needs?

 Contract packagers, such as Tjoapack, offer a wide range of services to drug manufacturers that they may not have been able to handle on their own. For example, a manufacturer may have a small-volume product or a unique pack-out that doesn’t fit into their existing capabilities or capacity. The contract packager is able to pool these together with other similar products from other manufacturers, making an investment into automation and technology more feasible (financially). In the end, the manufacturer is able to have their product packaged with a higher level of quality and with an overall reduced cost.

 Contract manufacturers typically run state-of-the-art production facilities that enable a wide range of services and packaging solutions. As a CDMO, we are a one-stop partner for our customers, offering services that range from clinical and commercial filling to final packaging solutions.

Having a proven track record demonstrates the ability of a CDMO to support customers’ special needs in secondary packaging. This includes production equipment for a broad range of order sizes and formats, broad expertise for country-specific needs, and extensive experience with international authorities. It also demonstrates leaner project coordination, streamlined fill-and-finish services, as well as reduced time to clinic and market. 


Vol. 46, No. 8
August 2022
Pages 47–48

When referring to this article, please cite it as S. Haigney, “Automating Packaging of Bio/Pharmaceuticals,” 

Automation of pharmaceutical packaging saves costs and time, say contract packagers.

Automating Packaging of Bio/Pharmaceuticals

 spoke with representatives from the European Directorate for the Quality of Medicines & Healthcare (EDQM), responsible for both the 

) and the Certificate of Suitability to the monographs of the 

 (CEP) procedure, about API quality from their perspective.

 How crucial is it for pharma manufacturers to ensure the safety of APIs?

 It is crucial that pharmaceutical companies select APIs of appropriate quality. In the [European Union], the marketing authorization holder/applicant is by law fully responsible for the quality of the API they use, since low-quality and/or ineffective APIs put the patients at risk.

 The requirements are well described in the international guidelines (ICH [International Council for Harmonisation]) that API manufacturers shall follow, in particular, ICH Q11 

Development and Manufacture of Drug Substances

Good Manufacturing Practice for Active Pharmaceutical Ingredients

ICH Q11 comprises crucial requirements related to manufacturing process development, description of manufacturing processes and process controls, approaches to developing a control strategy, critical quality attributes, [and] quality risk management.

API manufacturers [must] develop an appropriate manufacturing process for their APIs. During this step, knowledge about the API (e.g., its by-products and degradation products) is gained and an appropriate control strategy can be put in place for the next steps. An understanding of the manufacturing steps leading to the formation of impurities enables the implementation of appropriate steps and analytical controls to ensure that the API complies with the expected quality requirements.

Last but not least, API manufacturers have to work according to good manufacturing practice (GMP), as described in EU GMP Part II, which is equivalent to ICH Q7 (i.e., an appropriate quality management system).

 What are the steps sponsors should take to ensure the quality of APIs sourced from a supplier used in final products?

APIs used in the manufacture of medicinal products should meet quality standards, in particular pharmacopoeial requirements. In the countries which are party to the European Pharmacopoeia Convention, the legally binding quality standard is the 

 covers the API, the manufacturer of this API and the medicinal products produced using this API shall meet its quality standards. In cases where a specification contained in a monograph (of the 

 or in another pharmacopoeia) is insufficient to ensure the quality of the substance, the regulatory authorities may request additional specifications from the marketing authorization holder.

 ICH’s Q7A GMPs for APIs touches on all aspects of API production from facilities to equipment to materials management. Of all the areas the guidance covers, is there one particular aspect of API manufacturing that is more crucial for ensuring API quality?

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

) is intended to provide guidance for the manufacturing of APIs under an appropriate quality management system (QMS). This guideline has been introduced in the EU legislation as GMP Part II. The QMS should encompass the organizational structure, procedures, processes, and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. The QMS for APIs needs to be in place for all of these aspects—and if even a single aspect is neglected, the efficacy of the QMS based on ICH Q7 and the quality of the APIs are at risk.

 Clinical and non-clinical studies are performed on APIs during the development phases of a medicinal product to establish their efficacy and safety. Data thus gained are part of the submission for a marketing authorization and are reviewed by the respective regulatory authorities. If these studies show a negative balance for benefit-risk, the medicinal product will not obtain a marketing authorization—and will not be marketed.

Medicinal products that have obtained a marketing authorization are monitored for their quality, safety, and efficacy over their whole lifecycle. This system is in place to detect any issues that may negatively impact the benefit-risk balance. There are mandatory requirements for pharmacovigilance, with which marketing authorization holders must comply in order to monitor the safety of authorized medicinal products and detect any change to their risk-benefit balance. In case of a quality issue with APIs, the manufacturers must take appropriate action to address the issue, under the supervision of authorities (e.g., withdraw batches from the market).

Have regulators and industry resolved the nitrosamine problem or is it continuing? What steps can be taken to ensure a similar situation does not occur in the future?

 Regulators and industry are still acting to resolve the issue and the knowledge regarding their formation in APIs and in medicinal products continues to evolve. Nitrosamines in blood pressure medications are no longer a concern, since all measures to mitigate these impurities have been taken. However, nitrosamines may be found at very low levels in other medicinal products. Regulators have created international task forces (Nitrosamines Implementation Oversight Group, Nitrosamines International Strategic Group), elaborated regulatory guidance, and are sharing emerging information with each other in order to harmonize the actions to be taken.

Pharmaceutical Technology Europe spoke with representatives from the European Directorate for the Quality of Medicines & Healthcare (EDQM) about API quality from their perspective.