The development of complex biological drug substances such as monoclonal antibodies, interferons, peptides, vaccines, and ophthalmics is boosting demand for innovative delivery mechanisms (1). Many drug manufacturers are, therefore, opting for prefilled drug-delivery systems to administer new therapeutics. 

	However, employing prefilled delivery solutions can give rise to specific challenges. Particles can appear for a variety of reasons, during the manufacture, storage, or transportation of prefilled products. In turn, these particles can have an impact on the drug’s effectiveness. For example, if the particles are composed of large protein aggregates, the patient’s cells will only be able to partially absorb the drug or, for some products, will not be able to absorb them at all. Furthermore, particles can trigger unwanted side effects in the patient, such as autoimmune responses. 

	For the aforementioned reasons, authorities have-over the past few years-been steadily tightening up regulatory demands in regards to sub-visible and visible particles. Today, the authorities expect bio/pharma companies to develop, validate, and establish manufacturing processes, storage conditions, and transport operations in a manner that will eliminate the cause for the appearance of particles, as well as to ensure that particles and other contaminants are kept at a minimum. 

	Yet, for companies to be able to comply with the authorities’ expectations, deep knowledge of the processes involved is required. Additionally, identification and characterization of the particles are becoming ever-more significant. 

	The development of innovative analytical techniques has given rise to new investigative possibilities, in particular for sub-visible particles, which enable pharma and biotech companies to implement robust, high-quality processes for the manufacture of drug products in prefilled drug-delivery systems.

	There are different types of particles and different reasons why they are generated. Biologics are particularly prone to producing particulate matter.

	Extrinsic particles are foreign, additive particles and not part of the drug product formulation or primary packaging material. Extrinsic particles can result from the environment, such as cellulose fibers originating from disinfectant cloths, a human user, rubber, plastic, or metals. Because these particles arise externally, they may not be sterile and could be considered contaminants for the filled unit.

	Intrinsic particles are generated directly from the formulation of the drug product or during the manufacture of the drug product. Intrinsic particles such as protein aggregates may be the result of inherent properties of the drug product, interactions of the drug product formulation components or their contact with primary packing materials or processing aids. They may also emanate from the active drug substance.

	Inherent particles are generated from the formulation itself, for example, when an active substance or an excipient forms a haze or aggregates. This particle formation can be due to greater shearing forces, among other causes. Inherent particles do not affect the effectiveness of the drug and, therefore, do not have a negative impact on the patient.

	Air bubbles (as well as silicone oil droplets) are not particles per se, but almost all methods of analysis will reveal them as such because they are highly reflective. Air bubbles are most often generated by sample preparation.

	Silicone oil droplets specifically occur in syringes and cartridges, which, in contrast to vials, must be siliconized to enable the stoppers to glide smoothly in the glass barrels. Drops of silicone oil cannot be entirely avoided but they can be minimized. The amount of silicone oil applied can be reduced but only to the point that it does not impede break-loose and glide forces. This is a particular challenge for ophthalmic drugs.

	Particles also come in a variety of sizes. There are visible particles (approximately 100–150 µm and larger), which can be spotted with the naked eye during visual inspection and without any outside assistance such as magnifying glasses or microscopes. Conversely, subâvisible particles are in the nanometer to micrometer range. These particles include drug substance aggregates, silicone oil drops, fibers, and other materials. For injectables, the 

) defines, in chapter <788>, limit values for sub-visible particles equal to, or greater than, 10 μm (N = 6000) and 25 μm (N = 600) (2). The limit values for ophthalmic drugs are even more strict, namely equal to, or greater than, 10 µm (N = 50) and 25 µm (N = 1), see 

	Regulatory authorities, such as FDA, have tightened their requirements for the identification and characterization of particles over the past years, see 

<790> and <1790> (4,5). The authorities now offer a level of orientation when it comes to the visual inspection of filled units with regard to visible particles in injectable drugs. In addition, the sections of the corresponding pharmacopeias covering sub-visible particles are regularly reviewed and expanded where needed. The new guidelines require that companies not only discover the particles and sort out the visible particles contained in prefilled drug-delivery systems, but they also have to focus on particle characterization and root-cause analysis of particle type and source in commercial batches. The ultimate goal is to adjust manufacturing processes so that units contaminated with visible particles can be avoided altogether, and sub-visible particles are understood and avoided as much as possible. To understand the origin of particles, a close collaboration between different departments, such as development, manufacturing and quality control, is needed.

	There are a number of analytical approaches used for the determination, characterization, and identification of particles. The standard procedure to determine visible particles is a visual check of the filled units combined with a subjective description of any visible contaminants. Until now, the standard procedure for quantification of sub-visible particles in the micrometer range has been light obscuration. This technique, which is a compendial method for routine testing used in batch release, determines the number and size of sub-visible particles in the 1–100 µm range. However, the technique also has some limitations, especially since a description of the particle’s morphology and chemical characteristics is not possible. 

	Analytical labs are now establishing a range of novel analytical techniques to provide comprehensive particle characterization and identification, in particular, for sub-visible particles. These techniques are used primarily for testing and measuring the limits of the compounding, mixing, and filling procedure design during development. It is also possible to apply these techniques to any issues arising in commercial batches as they are capable of providing additional information that can be used to assist in performing a root-cause analysis. For example, these methods include the following (

Archimedes’ resonant measurement (Malvern Panalytical):

 This technique is used to detect sub-visible particles in the submicron range. Particles between 50 nm and 5 μm are transported through a mechanically resonating microfluidic channel. The mass, dry mass, and size of particles are calculated. The detection of particles with different buoyancy makes it possible to distinguish extremely small sub-visible particles such as a drug protein aggregates from silicone oil droplets.

Micro-flow imaging (MFI, Protein Simple):

 MFI combines the possibilities of digital microscopy with modern microfluidics, producing high-resolution images of sub-visible particles between 1 μm and 70 μm. Image analysis permits the determination of the morphology, intensity, and coincidence of particles. This, in turn, provides information about the particle type (e.g., air bubble, silicone oil droplet, protein aggregate, or fiber). Therefore, by combining information about particle number and size with information about particle shape and transparency, morphological data can be generated that will characterize individual particle subsets by using a modern application software.

 This approach combines the automated static imaging capabilities of a high-resolution, modern digital microscope with the chemical identification of individual particles using Raman spectroscopy. This method is suitable for sub-visible and visible particles because it can be used to classify particles over a very wide range (1 μm–1000 μm) by size and morphology, as well as chemically by means of Raman spectra.

ETAC Proview (Bosch Packaging Technology):

 This computer-based automated inspection system, a digital visual inspection at laboratory scale, is used for research and development, and enables objectification of the manual visual inspection. Photos and videos can be made of filled units from different perspectives using two cameras and a range of lighting options. Application software permits the precise evaluation of visible mobile and immobile particles in each unit. By contrast, the human eye can only count up to a limited number of particles (

	One effective way to gather reliable data when identifying and characterizing particles is for the outsourced service to create a team of experts with comprehensive knowledge of a specific topic (i.e., particulate matter). Each new project will then further expand the formed team’s knowledge. By using innovative analytical equipment the team will be able to perform most of the analytical methods used in the field of particle measurement.  

	Through the use of a specific team of experts and by expanding the team’s knowledge on particular topics, reliance on an additive external laboratory, which requires greater organizational effort and additional sample shipment, may be circumvented as everything can be achieved via a single outsourced service provider. As the specialists come to know the manufacturing processes, they can continuously optimize the analytical services and offer a range of support to help meet the challenges inherent to the topic of particulate matter.

	The number and types of biological drugs in development are constantly growing which, in turn, fosters stricter guidelines from regulatory authorities, especially with regard to particulate matter. Manufacturers will need to adjust their analytical techniques as well as production processes to quickly identify and reduce the causes of particle generation. 

	As a result of the need to adjust techniques and processes, analysis and characterization of particles have become a priority. By drawing on technological advances, the latest methods of analysis, and experienced specialists, bio/pharma companies will not only gain insights into the types and sizes of particles, but will also be able to perform fast and efficient root-cause analysis. 

	Manufacturers of parenteral drugs will benefit in the long-term from detailed data about the processes involved in commercial manufacturing. These manufacturers will also be able to comply with the stricter regulatory guidelines and customer demands while maintaining high quality standards. 

	1. K.J. Wrigley, Pharm. Tech., 41 (10) 32–35 (2017).
	2. USP, 

 General Chapter <788>, “Particulate Matter in Injections” (US Pharmacopeial Convention, Rockville, MD, 2012).
	3. USP, 

 General Chapter <788>, “Particulate Matter in Ophthalmic Solutions” (US Pharmacopeial Convention, Rockville, MD, 2012).
	4. USP, 

 General Chapter <790>, “Visible Particulates in Injections” (US Pharmacopeial Convention, Rockville, MD, 2014).
	5. USP, 

 General Chapter <1790>, “Visual Inspection of Injections” (US Pharmacopeial Convention, Rockville, MD, 2015. 

	When referring to this article, please cite it as M. Maier and M. Zerulla-Wernitz, “Analysis of Sub-Visible Particles," 

is head of the Analytical Science Laboratory, Project & Service Analytics, Vetter Pharma-Fertigung GmbH & Co. KG

Articles

Features

Novel analytical methods may help biologics manufacturers respond to stricter regulations on particulate matter.


Analysis of Sub-Visible Particles

-century biopharma, no longer is “bigger” viewed as “better.”  Many small pharma and biotech companies operate with leaner, often virtual company structures; tight budgets and timelines; and results-oriented cultures. Consequently, to advance pipeline products from research to preclinical, partnering with contract development and manufacturing organizations (CDMOs) is necessary, and assembling a robust technology transfer package is key to success. This article shares some best practices for technology transfer based on lessons learned in transferring an early-stage cell culture process to a CDMO for Phase I clinical manufacture.

	During the lifecycle of a typical manufacturing process, there will come a point where it must undergo a technology transfer. In the case of large pharma, this often occurs internally from the development team transferring a lab-scale process to the manufacturing team to scale it up. For smaller companies that lack a good manufacturing practice (GMP) infrastructure to produce their drug products for clinical studies, they must transfer their process to a CDMO to produce material to fuel preclinical and Phase I studies. 

shows a typical tech transfer process flow. Depending on experience, each company uses its own technology transfer methodology, comprised of internal expertise and proven rules-of-thumb.

	During early drug development, successful selection of a CDMO can be difficult for a number of reasons. Manufacturing schedules are often set years in advance, costs can be high and, depending on how established a CDMO is in the industry, the level of experience and expertise can vary. Smaller companies are often under a tight timeline with a limited budget. So, when choosing a CDMO partner, it is important that they have experience working with smaller companies and have a solid technical team that is accustomed to rapid decision-making, with the ability to solve the types of technical problems that occur during development and manufacture. 

	Assemble the team with communication in mind

	Successful technology transfer depends on reliable communication, planning, and documentation executed by results-oriented team players, which involves assembling appropriate members from both sites (sponsor and CDMO), ideally with each member having a counterpart to ensure direct transfer of knowledge and good communication.  Depending on the CDMO, there may be separate teams for manufacturing and process development. Be sure that both groups have representation because when problems arise, the two groups must communicate well with each other so that the flow of information continues.

	As an example, in one case a sponsor called the his CDMO counterpart in the middle of the night to say that an operator had added the wrong amount of feed medium to a production run. It turned out that the scale had been incorrectly calibrated and was measuring in pounds instead of kilograms. Fortunately, this error was caught early enough to fix it by performing a quick calculation and adding the remaining amount. It was also fortunate that the sponsor knew he could call his CDMO at any time. The lesson is: be sure the technical team is able to ask their counterparts questions to assess compatibility and gauge experience with similar products. Find out how they troubleshoot when problems arise. Make sure they have a scale-down model. Ask to view some blinded data from a previous tech transfer or scale-up. In this type of endeavor, a picture is worth 1000 words.  

	Process knowledge and documentation: completeness is vital

	Assembling a robust and complete documentation package is crucial to the success of any tech transfer. A well-developed tech package will enable a project to be transferred with a minimum of setbacks. Sometimes small companies try to capture everything in their technology transfer documentation for early-phase tech transfers. They will often have stability data, a complete set of analytical methods, and complete product specifications. And there is nothing wrong with having all of that because it will be useful for later phases (Phase II/III) in a product’s lifecycle, even if it isn’t necessary for early drug development. Keep this in mind, as it can save time. A typical early-phase technology transfer package includes at minimum the following documents:

		Product characterization data: The sponsor must provide a quality target product profile that includes critical quality attributes (CQAs), release specifications, and any preliminary stability information.

		Process description: It is the responsibility of the sponsor to provide a detailed description of the final process they would like to transfer. The process description should contain all process parameters and conditions and CQAs, and it should be as detailed as possible. It should also include any lab or small-scale batch records as well as a discussion on any critical operating parameters.

		Process development and cell line development reports: The process development site must document why certain decisions were taken and why certain parameters or conditions were selected while others were not during process development. Availability of this document to the CDMO allows understanding of critical process parameters and enables decisions about how to execute each process step with acceptable margin of all parameters and conditions. If at all possible, it should include a scale-up rationale and any pilot batches conducted.

		A brief description of analytical procedures with proposed specifications and acceptance criteria: Keeping in mind that this stage is early drug development, it is not expected that all methods and specifications be defined for a Phase I biologic. For a Phase I biologic, analytical methods should be in place; however at this early stage, they do not need to be validated. 

	There is an expectation that throughout the development lifecycle, the manufacturing process will evolve and improve with gained knowledge from more production batches, which also holds true for the analytical methods associated with the product. Often small companies do not have this in mind and invest more time than is merited based on the phase of their product. Extensive process and product characterization becomes more important for Phase II and Phase III products.

	After completing document and knowledge transfer, the CDMO will typically perform a facility fit assessment to discern any additional gaps and risks. This exercise involves a step-by-step analysis of how the entire manufacturing process would be performed at the CDMO with the goal of identifying any potential process, facility, or procedure changes needed to fit the process into the CDMO’s facility. The output of the facility fit analysis should be a comprehensive list of possible gaps and should be jointly developed by both the sponsor and the CDMO. Typically, formal summaries and process flows are provided, including suggestions on how to adapt the process to the CDMO’s facility and equipment as well as an experimental plan to test potential new procedures at small scale. Once the knowledge/documents have been transferred by the sponsor to the satisfaction of the CDMO, the identified activities required to confirm the transfer are completed, including closing gaps and reducing risks.

	Demonstration batches are a must, ideally at-scale

	Take the time to do a demonstration batch that incorporates all of the process design batches that were conducted to address facility fit gap. One item most worth spending the money on is an at-scale engineering batch. An at-scale engineering batch may appear to be costly, but it saves time for subsequent batches. It allows for extra in-process sampling, refinement of manufacturing batch records, and related GMP documentation, adjustments to the process as required by facility and equipment differences, and a reduction in the cost of the initial, high-risk, full-scale production. By running at least one such batch at scale and adjusting some parameters based on the data from that run, a company can reduce the risk of its initial GMP batches failing. 

	No technology transfer is perfect. It is inevitable that issues and problems arise. The best advice is to keep communicating. When there are oddities in a batch, people may get defensive-particularly if the batch does not meet specifications, or if there were anomalies along the way that were not reported to the sponsor. Identifying a CDMO that is of a similar mindset, has good communication, and is accountable when issues come up is key. 

	When referring to this article, please cite it as B. Fallentine, “Mind the Gap: Tech Transfer from Early Stage Cell Culture to Phase I Clinical Manufacture," 

	Barrett Fallentine is director of Product and Process Development, Pharmatech Associates, 

Tech transfer is key to succession advancing biopharmaceutical pipeline products from research to preclinical.

Mind the Gap: Tech Transfer from Early Stage Cell Culture to Phase I Clinical Manufacture

With many gene and cell-therapy drugs in development, there is an increased need for scientific expertise to develop new bioanalytical technologies as well as use existing platforms such as quantitative polymerase chain reaction (qPCR) and flow cytometry within the regulated bioanalytical space. Current FDA guidance provides little direction on how to approach assay development and validation when using these emerging technologies, nor is there guidance for the application of more familiar technologies to gene-therapy applications. It is important to understand the complex assays needed for these programs and work with partners that provide expertise to ultimately expedite these highly complex therapeutic classes.

	Specialty assays used to understand the distribution, function, efficacy, and immunogenicity of gene- and cell-therapy drugs-including cell-based neutralizing assays, qPCR, flow cytometry and enzyme-linked immunosorbent assays (ELISA)-are discussed, as well as recommended strategies for development, validation, and implementation of assays for sample analysis from regulated non-clinical and clinical studies.

	Cellular and gene therapies are not new to the medical establishment. Cellular therapy, the transfer of live cells with a specific function to a patient to treat/cure a disease, was first successfully used in humans in the early 19th century in the form of blood transfusion. Bone marrow transplants, a similar form of treatment, have become relatively common since the initial reported use in 1968.

	Gene therapy, the transfer of genetic material into specific cells to modulate gene expression or produce a new/modified protein, was first tested in a clinical trial in 1990 (1). Researchers at the National Institute of Health’s Clinical Center treated two children with adenosine deaminase deficiency using the patient’s own white blood cells that had been harvested, had normal genes inserted, and were reinjected into the patient.

	Since 1990, due to improved understanding of the human genome, proteome, and immune system along with improved drug delivery processes, the safety, efficacy, and applicability of cellular and gene therapies seem to be truly coming of age.

	Both types of therapy have been shown to cure or mitigate the underlying cause of genetic and acquired diseases by replacing missing proteins or cells, modulating expression of specific proteins, and/or selectively killing tumor cells. Challenges remain for development of these therapies, particularly in the bioanalytical method approach required. Questions include the following:

		How much of a dosed gene therapy is present in circulation, in the target tissue, and how long does it stay there?

		Is the target protein expression changed per the drug mechanism?

		Is the vector genome released (shed) from the patient, allowing for potential transmission to other humans or the environment?

		For cell therapies, do the transferred cells survive and do they express the appropriate markers?

	The assays used to measure these characteristics are often not traditional liquid chromatography–mass spectrometry (LC–MS) or ELISA used to quantify small- and large-molecule therapeutics and biomarkers. The May 2018 FDA Bioanalytical Method Validation (BMV) Guidance for Industry (2) provides general guidelines for all bioanalytical assays but lacks any specifics on assays that use flow cytometry, PCR, protein expression/activity, or other techniques. This leaves investigators asking questions about how to demonstrate the key bioanalytical attributes specified in the guidance, namely demonstrating that the method measures the intended analyte, evaluating assay variability, the range in measurements that provide reliable data, and the effect of sample collection, handling, and storage on the reliability of data.

	For gene therapy programs, one of the first considerations is the biodistribution of the dosed vector and genetic material (3,4). The biodistribution assay will indicate whether the target tissue is successfully transduced by the vector and, if so, how much is present within the tissue. The assay will also determine whether other tissues beyond the specified target are affected; off target transduction will result in toxicity. It is especially important to assess whether the vector reaches the gonads and, if present, whether it is in the germ cells that can result in transmission to the next generation. Sampling from biodistribution studies should be performed at multiple time points and should include time of expected peak concentrations along with multiple late time points to determine both distribution/presence and clearance of the dosed gene therapy. Both the vector and transgene should be evaluated.

	Quantitative PCR is typically used for the biodistribution assay because of sensitivity requirements. Assay validation includes evaluation of intra- and inter-assay precision and accuracy, specificity and selectivity, limit of detection, and stability. Expression of the gene therapy product should also be considered, to help determine whether the transgene protein is expressed or if the target protein expression is altered per the dosed gene therapy. The expression may be assessed via a standard ELISA; the current 2018 FDA BMV guidance (2) provides specific assay parameters to validate. These parameters include intra- and inter-assay precision and accuracy, dilutional linearity/integrity, selectivity, and stability, with acceptance criteria of ± 20% bias and ≤ 20% coefficient of variation applied (25% at the lower and upper limits of quantification). In some instances, the activity of the protein may be beneficial to assess, and similar validation parameters and acceptance criteria are generally straight-forward to apply.

	Another important assay for gene therapy programs is immunogenicity both to the viral vector and to the product of the transgene. Most of the vectors utilized are likely to have modifications that will trigger the host to recognize it as “foreign” and elicit an immune response that may change the clearance of the vector prior to proper transduction or produce neutralizing effects. In addition, many of the viral vectors may react with antibodies already present in animals and humans. To prevent these pre-existing antibodies from interfering with the program, it is recommended to pre-screen the sample population, and often individuals with high titers of antibodies are excluded from the program.

	The assays used to assess immunogenicity are standard ELISAs, cell-based assays are preferred to determine neutralizing effect. The 2016 draft FDA immunogenicity guidance (5) provides the necessary assay parameters to be evaluated, including cut point determination, intra- and inter-assay precision, sensitivity, drug tolerance, specificity, and selectivity. At a minimum, the screening and confirmatory assays should be performed, and when needed, the anti-drug antibodies can be further characterized by performing titer and neutralization assays.

	If the delivery mechanism is a viral vector, to determine whether the vector genome was released from the patient resulting in the possibility of horizontal transmission, then viral shedding (release of the vector genome from the patient) should be evaluated to determine the possibility of transmission to other individuals and to the environment. A quantitative approach is recommended, and therefore, qPCR is typically used. Matrices such as urine, saliva, and nasal swabs are tested to determine whether horizontal transmission of the viral vectors occurred. A guidance for this assessment was released in 2015 by FDA (6).

	Cell-therapy products have evolved from blood, bone marrow, and stem cells to more complex engineered autologous or allogenic immune cells to treat cancer. Cell-therapy products that meet the definition of “biologic product” require complex analytical strategies and unconventional bioanalytical methods to determine distribution and persistence of the product. In the case of chimeric antigen receptor T (CAR-T) cells, the construct and viral vector used for transduction are key in determining the design and type of assays required. The bioanalytical methods for these types of programs typically require flow cytometry, qPCR, and immunogenicity assessments.

	The first consideration is the development of reagents to be used as controls within the assays. The time upfront in production and characterization of high-quality reagents will result in reduced cost and timelines for the program. Experiments to develop the methods should be carefully thought through to ensure all parameters are evaluated prior to proceeding to validation. High sensitivity methods are required especially when evaluating the expansion and persistence of the CAR-T cells. When considering the development of flow cytometry methods to detect expression of the CAR, optimal antibody and fluorochrome combinations are determined, antibodies are titrated to maximize sensitivity and specificity, and appropriate controls are incorporated (i.e., fluorescence minus ones, experimental procedures for lysing, washing, fixation, intra- and inter-assay precision, limit of detection, inter-instrument assessments, and stability). qPCR method development and validation is similar to that described previously for gene therapy programs. Immunogenicity assay development and validation will follow the recommendations in FDA’s 2016 draft guidance (5); however, one consideration is the detection of antibodies to multiple sequences within the CAR construct that likely will be considered foreign to the recipient’s immune system (i.e., anti-viral protein response).

	Platforms for gene- and cell-therapy programs

	The choice of platform is primarily driven by and unique to the bioanalytical needs of the gene- and cell-therapy product under development. Specificity, selectivity, and sensitivity requirements also weigh heavily into the final decision. Irrespective of the platform, the choice of reagents has a significant impact on specificity and sensitivity, and therefore time and effort are well-spent in identifying and securing a sufficient and well-characterized supply of reagents to support the lifecycle of all bioanalytical methods.

	qPCR is used to quantify a viral genome in serum, tissue, or body fluids for the purpose of pharmacokinetics (PK), biodistribution, or vector shedding evaluations (3,4,6). It is also used to measure the expression levels of transgene- expressed mRNA in target tissue for gene therapy programs. PCR is a widely used platform; however, there is a lack of specific regulatory guidance and industry standards for development and validation. The 

Minimum Information for Publication of Quantitative Real-Time PCR Experiments

 (MIQE) guidelines published in 2009 (7) were designed to standardize nomenclature, design, and interpretation of qPCR experiments, and provide a valuable reference in the absence of other publications.

	Flow cytometry platforms can measure multiple parameters within a single analysis, and it is a powerful tool for cell-therapy programs. The technology allows for real-time monitoring of the cell therapy 

 and can support the qPCR data for PK. Flow panels can be designed to evaluate the expression and persistence of the construct over time but can also provide insight into the immune activation status by the addition of antibodies to known markers on lymphocytes. Stability of samples need to be taken into consideration when performing flow for cell-based therapies. To maintain sample integrity, in most instances, samples need to be analyzed within 24–48 hours, which can lead to logistical challenges. The European Bioanalysis Forum released a white paper in 2017 (8) with the intent to provide practice guidance on the use of flow cytometry for regulated studies that support drug development programs. The paper addresses the use of flow cytometry from a bioanalytical perspective and addresses additional parameters not discussed in previous publications.

	In genome-editing applications, newer, rapid-sequencing platforms such as next-generation sequencing (NGS) offer techniques to monitor both the efficacy of editing as well as potential off-target gene edits. These technologies are challenging to validate and therefore are typically performed in a non-good laboratory practice fashion. There currently are no regulatory guidance documents that govern this body of work; however, as NGS is used in clinical laboratories for diagnostic purposes, published guidelines (9) governing that work may be leveraged where and when appropriate.

	Tried and true platforms such as ELISA maintain a presence in the gene- and cell-therapy bioanalytical space due to relatively low cost, ease of use, and solid performance. ELISA assays can be applied to the detection of anti-capsid or anti-transgene antibodies, and to detection of antibody responses to other components of the gene or cell therapy that may possess immunogenic potential. A requirement for enhanced sensitivity may benefit from newer technologies such as electrochemiluminescence or resonance-based platforms. These newer platforms also offer the advantage of being species-agnostic and therefore can be used throughout the nonclinical and clinical continuum. FDA, along with other global regulatory bodies, have published specific guidance documents for the development, validation, and assessment of anti-drug antibodies (5). Effort should be made to adhere to these guidance documents in the assessment of immunogenicity to gene and cell-therapy elements.

	In some situations, the nature of the therapy, molecule, disease, or patient may dictate the need to derive a fit-for-purpose approach to immunogenicity assessment. Cell-based assays provide an essential platform for the detection of neutralizing antibodies. Cells that are permissive to transduction by the viral vector are exploited for this purpose in gene therapy programs. To-date, the design, execution, and reporting of data from these assays has not been standardized, making comparison across studies challenging.

	Commercial ELISA kits can be used for the quantification of the newly-expressed protein resulting from gene therapy. In this setting, the measurement of expressed protein is considered a biomarker, and the assay should be validated to the requirements specified in FDA’s May 2018 bioanalytical guidance (2).
	More recent technologies such as Simoa (Quanterix) and SMC Errena (Singulex) instruments promise ultra-high sensitivity, which is an advantage when trying to quantify the typically very low levels of protein. Recently, the market has seen an increase in highly sensitive commercial ELISA kits and chemiluminescent and fluorescent substrates that also enhance sensitivity. Other platforms can be applied to the functional assessment of expressed proteins; examples include clotting time for expressed coagulation factors or substrate cleavage by expressed enzymes. FDA released guidance on biomarker evidentiary framework (10) that describes a recommended approach for analytical biomarker assays.

	With the newer generation and more complex gene and cell-therapy products in development, it is important to seek scientific expertise to plan and design what is needed to develop and validate the bioanalytical methods required to achieve an overall successful program.

. 270 (5235), 475–480 (1995).
	2. FDA, 

Guidance for Industry: Bioanalytical Method Validation

Guidance for Industry: Gene Therapy Clinical Trials-Observing Subjects for Delayed Adverse Events

 (Rockville, MD, November 2006).
	4. FDA, 

Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products

 (Rockville, MD, November 2013).
	5. FDA, 

Draft Guidance for Industry: Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products

Guidance for Industry: Design and Analysis of Shedding Studies for Virus of Bacteria-Based Gene Therapy and Oncolytic Products

 (Rockville, MD, August 2015).
	7. S.A. Bustin et. al., 

. 55(4), 611–622 (2009).
	8. B.V. Der Strate, et. al., 

. 9(16),1253-64 (2017).
	9. R. Somak, et. al., 

Guidance for Industry and FDA Staff: Biomarker Qualification: Evidentiary Framework

	Christina Satterwhite, PhD, is senior director, global laboratory sciences; Jessica St. Charles is director, laboratory sciences; Valerie Theobald is director, immunoanalytical services; and Jenifer Vija is scientific director, bioanalysis, all at Charles River Laboratories.


	Supplement: Partnering for Bio/Pharma Success 2019
	February 2019
	Pages: s24–s26, s31

	When referring to this article, please cite it as C. Satterwhite, et.al., "Emerging Therapies Test Existing Bioanalytical Methods," 

Pharmaceutical Technology's Partnering for Bio/Pharma Success

Drug developers must understand the complex bioanalytical assays for cell- and gene-therapy drug development programs and ensure that partners have the specialized expertise needed for complex therapeutic classes.

Emerging Therapies Test Existing Bioanalytical Methods

Innovation in the bio/pharmaceutical industry brings success to pharma companies and new options for patients. New treatments and therapies, however, often come with new and/or additional analytical testing requirements. Many bio/pharmaceutical companies don’t have the knowledge, experience, instruments, or personnel to perform such testing; therefore, many analytical processes are outsourced to contract research, contract development, or contract manufacturing organizations (CROs, CDMOs, CMOs). And outsourcing of these and other services is expected to grow in the coming years (1).

	So how can contract laboratories serve the pharma industry? 

 spoke with Kimberly McClintock, executive vice-president at Metrics Contract Services, which offers method development and validation for small-molecule drug substances and drug product stability and release testing including on-site microbial testing; and Patrick A. Tishmack, PhD, analytical services general manager at AMRI West Lafayette, which offers both small- and large-molecule analysis, about the benefits of outsourcing analytical processes and testing. 

Why should pharmaceutical companies outsource their analytical processes?

One of the main reasons to outsource laboratory testing is to access expertise and instrumentation. It may not be feasible for pharmaceutical companies to purchase and operate specialized equipment themselves for a limited number of programs. Contract labs support hundreds of programs, making significant investments worthwhile and enabling them to hire and retain qualified, experienced staff for specialized testing. Examples of this include inductively coupled plasma-mass spectrometry (ICP–MS) and inductively coupled plasma-optical emission spectrometry (ICP–OES), which are used to detect elemental impurities.

	Working on a wide variety of programs gives contract labs an advantage for problem solving and regulatory compliance. Frequent inputs from global regulatory agencies and client quality departments give contract labs a strong sense of industry expectations and numerous examples of how to plan, execute, and report method development and testing that is acceptable for submission.

 Certain analytical techniques are more conveniently outsourced because they may be tedious or require significant overhead or training that could distract from a company’s focus.  This might include potent compounds, controlled substances, or other special handling requirements such as inert atmosphere.

	Virtual companies that do not have any internal analytical capabilities usually call on one or more contract research organizations to do all of their analytical testing.

	Larger pharmaceutical companies may want to outsource certain types of analytical testing to be done in parallel to internal studies for validation or troubleshooting.  Outsourcing is also a good way for a pharmaceutical company to expedite development timelines or to move lower priority development out of their laboratory so that there will be some progress when it eventually becomes a higher priority.

 Which small-molecule analytical services should pharma companies consider outsourcing?

 Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry are commonly outsourced because these capabilities are typically quite expensive to acquire and maintain. Both techniques usually require experts to properly maintain the instruments and to implement advanced applications that will obtain maximum value from the techniques.

	Elemental analysis and metals analysis are very commonly outsourced, particularly if GMP compliance is needed.  Carbon, hydrogen, nitrogen, and sulfur analyses are relatively simple to perform, which means that high volume is the only economical way to use the instrument.  Metals analysis by ICP–MS or ICP–OES may be more conveniently outsourced due to the acid hydrolysis procedure needed for sample preparation and the instrument maintenance requirements.

 Which large-molecule analytical services should biopharma companies consider outsourcing?

 Mass spectrometry is typically used for peptide mapping and protein sequencing, which requires a high-performance instrument and an experienced scientist. 

	NMR spectroscopy of large molecules is still a very specialized technique that requires a highly skilled scientist with specialized training to collect good quality data and to properly interpret the complex NMR spectra.  Therefore, relatively few CROs have this capability.

	Capillary electrophoresis, particularly combined with mass spectrometry, is a high-value analytical technique for most biologics and larger molecules.  This technique is very useful for difficult separation and characterization procedures.

	Cell-based assays can be quite difficult to develop and validate, so an experienced CRO will expedite biologics development and preclude the need to invest in the specialized infrastructure required for maintaining cell lines.

 What are the downsides to outsourcing analytical services?

 Analytical methods and results are a critical part of product development, so outsourcing this work could create a gap for the pharmaceutical company.  A strong contract lab partner will make sure the sponsor understands more than just the values reported. For example, the contract lab will convey observations made during dissolution since these can be critical to assessing whether the formulation and process are robust.

	Best practices for outsourcing analytics

 What are some best practices for data integrity and tech transfer when it comes to outsourcing analytical services?

 It is a tech transfer best practice to completely evaluate method(s) being transferred for method competency and successful transfer.

A highly competent quality unit is a key indicator that the CRO knows what it takes for appropriate regulatory compliance.  A good indicator that a CRO has adequate control over their processes is the existence of a laboratory information management system (LIMS), particularly if nearly all laboratory processes, data integrity, and quality assurance procedures are integrated into it.  A critical consideration is determining if the CRO has electronic records that are created and maintained by software with rigorous user access control, extensive audit trailing, and secure archiving of data files.  It is also very important to determine whether the CRO has experienced scientists with extensive training who can provide expert analytical method development and validation under GMP compliance.

 Which outsourced analytical services are in high demand?

 We are seeing high client demand for residual solvents, elemental impurities, API solubility and dissolution method development, and API characterization.

 Unknown particle identification, NMR spectroscopy of solids and liquids, chromatography, and mass spectrometry have all been growth areas, especially non-routine testing to solve unusual problems.

 Are there analytical processes not currently being outsourced that you anticipate will be in the future?

 Pharmaceutical companies typically adopt new analytical techniques rather quickly, but they tend to rely on them for release testing of drug substances and drug products only after significant assurance of reliability.  Although nearly every common analytical technique can be outsourced if desired, many pharmaceutical companies are selective in the types of analyses outsourced to a CRO depending on their own experience and internal capabilities. 

	Selective outsourcing of biologics testing is quite common because pharmaceutical companies are reluctant to rely on potentially less experienced CROs to transfer or develop analytical methods for biologics that are difficult and expensive to make and test.  Atypical analytical techniques that are still in the development stage may eventually be outsourced once they have been better established as suitable tests for pharmaceutical development.

	            1.         R. Rader and E. Langer, “The Outlook for CMO Outsourcing in 2019, 

	When referring to this article, please cite it as S. Haigney, “Utilizing Analytical Services for Success in Innovation," 

Outsourcing of analytical testing and processes can help bio/pharmaceutical companies expand their product profiles. 

Utilizing Analytical Services for Success in Innovation

spoke with John Pirro, senior director of large molecule bioanalysis at WuXi AppTec, which provides anti-drug antibody (ADA) and neutralizing antibody (Nab) assay development, validation, and sample analysis services, about best practices to ensure that biologics are safe and effective.

 Immunogenicity refers to the ability of an antigen to induce an immune response. Biological products with an increased potential for eliciting ADAs include therapeutic antibodies, enzyme therapies, peptides, and combination products. ADA can reduce the ability of the drug to reach the intended target, alter the PK [pharmacokinetics] profile, and potentially mediate serious adverse effects. A subgroup of ADAs, which are called neutralizing antibodies, can also cause potentially serious adverse effects.  

 Which immunogenicity testing methods are used to determine immunogenicity profile of a biologic? How do these methods differ, if at all, for biosimilars?

 In practice, immunogenicity is assessed by the detection of antidrug antibodies using a positive control antibody, representing a potential polyclonal antibody in a biological system. There are many different types of assays ranging from classic ‘bridging’ assays to more complex ‘bead acid dissociation’ assays.

	Which assay to use depends on the reagent you use as a positive control and the baseline immunogenicity of the drug in question. The methods can differ depending on the type of biosimilar (modified to stay in plasma longer) to other types of biologics (bi-specific antibodies) depending on the makeup of the biologic and the method of action. You must have experience in all forms of assays for immunogenicity to modify the design to fit each case.  

 How does immunogenicity testing differ when dealing with antibodies compared to other biologics?

 For non-antibody biologics, test development needs to emphasize the fact that non-human amino acid sequences are often used to modify the protein, and these sequences are typically immunogenic. It’s important to use polyclonal antibodies as positive control. For antibodies, testing differs depending on the site of modification (Fb region for bi-specific), attachment sites for antibody drug conjugates, and whether it is a fusion type of antibody design. Special considerations have to be taken with these types of biotherapeutics, specifically around the reagents used to capture and detect the biologic. It is in this case that the use of monoclonal antibodies and IgY antibodies come into use. 

What mistakes do companies make when performing immunogenicity testing?

 The usual mistake is in the design of the ADA assay (lack of Domain ADA assays for fusion proteins, etc.) or in the reagent they are using to detect or capture the biotherapeutic. For example, using a monoclonal antibody when you should use polyclonal antibodies or not considering the use of IgYs to develop positive controls, which do not bind to rheumatoid Factors; the determination of the positive control for ADA or Nab assay; and not understanding that you will have to re-determine the cut point with disease state serum from the study.

	When referring to this article, please cite it as S. Haigney, “Xxxxxxx," 

Pharmaceutical Technology spoke with John Pirro, senior director of large molecule bioanalysis at WuXi AppTec, which provides anti-drug antibody (ADA) and neutralizing antibody (Nab) assay development, validation, and sample analysis services, about best practices to ensure that biologics are safe and effective.

Best Practices for Immunogenicity Testing of Biologics

spoke with Lisa Crandall, MS, associate director CMC Project Management, and Peter Angus, PhD, director of Pharmaceutical Sciences, at Velesco Pharma, which provides a full range of stability testing of API and drug products, about best practices in stability testing.

 Which methods are used to determine stability of a drug in early development? In later-stage development? Do these methods differ?

 In early development, typical API and drug product stability analysis include appearance, assay, related substances, and water. Additionally, depending upon type of drug product formulation being assessed, tests such as assay of preservatives and/or antioxidants, pH, viscosity, osmolality, particulates, antimicrobial effectiveness, and microbiological bioburden may be necessary. Specific methods such as high-performance liquid chromatography (HPLC) for assay/impurities are phase appropriate.  In later development, the stability indicating techniques haven’t changed, but the specific methods have evolved with the product.  Quantitation of known impurities is now possible.

What steps should be taken to ensure stability of a drug?

 To increase the chances that your drug is stable, it is vital to pay attention to all early data pertaining to the effects of temperature, humidity, light, polymorph, salt form, etc., as well as excipient compatibility and packaging. Discovering limitations and interactions early in development provides a better chance of success, especially in situations in which one polymorph is significantly more stable than others.

 What mistakes do companies make in early development that could lead to instability?

 Common mistakes early in development are ignoring the importance of risk assessment using the philosophies in International Council for Harmonization (ICH) Q8 and Q9, and not allowing enough time for designing a quality product. With appropriate foreknowledge, many drug instability challenges can be overcome by designing the synthetic route, formulation, packaging, storage, etc., with the future in mind.

What are some best practices for ensuring product stability in both early and later-stage development?

 To ensure the best chance for a successful and stable product, it is important to design early phase experiments to provide as much understanding about the API and product as possible. As the product progresses, it is important to use and build upon the data in hand to make necessary adjustments to synthetic routes, formulations, manufacturing processes, packaging, and analytical methods.

	When referring to this article, please cite it as S. Haigney, “Determining Drug Stability," 

Pharmaceutical Technology spoke with Lisa Crandall, MS, associate director CMC Project Management, and Peter Angus, PhD, director of Pharmaceutical Sciences, at Velesco Pharma, which provides a full range of stability testing of API and drug products, about best practices in stability testing.

Determining Drug Stability

Over the past few months, contract manufacturing organizations (CMOs) and other contract service providers have expanded, invested, and acquired companies to increase pharmaceutical service offerings. The following news updates highlight such efforts.

MedPharm, a contract provider of topical and transdermal product design and formulation development services, announced the expansion of its center of excellence in Durham, NC (1).

	The $4-million expansion includes additional laboratory space for development programs and topical dosage formulation development services and performance testing on topical and transdermal pharmaceutical products. The investment in facility expansion and equipment will more than triple the existing footprint of the facility to 25,000 ft

	The company has also increased its liquid chromatography–mass spectrometry (LC/MS) capacity and the automation of sample handling. As part of the investment, MedPharm has installed the latest Waters LC-MS/MS for bio-analysis. This new model is equipped with the latest ultra-performance liquid chromatography for rapid separation and method development and offers mass spectrometry detection at picogram levels, according to MedPharm.

	“This expansion aligns with MedPharm’s strategy to keep increasing the sophistication and relevance of our proprietary 

human skin models and further increase our responsiveness to clients in formulation development, especially in ocular delivery,” said Eugene Ciolfi, MedPharm’s president and CEO, in a Jan. 11, 2019 press release. “The expansion complements the recent expansion we have completed in our facility at our headquarters in Guildford, UK, and reflects the positive demand for our services globally.”

Catalent, a provider of delivery technologies and development solutions for drugs and biologics, is set to invest $200 million in its biologics business to expand drug-substance manufacturing capacity and drug-product fill/finish capacity (2).

	Spanned over a three-year program, the investments will be carried out at the company’s biologics manufacturing sites in Madison, WI, and Bloomington, IN. The expansion includes the increase of mammalian cell-culture capacity at the Madison site, where the company will build-out two new suites, each with a 2 x 2000-L single-use bioreactor system, providing additional clinical and commercial production capacity at the 2000- or 4000-L batch scale as well as new laboratories. Work is expected to be completed by mid-2021 and will more than double Catalent’s commercial biomanufacturing capacity, the company reports.

	Additionally, the company will expand fill/finish capacity at the Bloomington site by 79,000 ft

, with both GMP and non-GMP capabilities. A high-speed flexible vial line, using both ready-to-use components and bulk filling at a filling speed of 300 units per minute, will be installed along with a high-speed flexible syringe/cartridge line with a filling speed of over 300 units per minute, and a fully automated vial inspection machine.

	In December 2018, Catalent also announced plans to invest $14 million in packaging capabilities at the Bloomington site (3). Construction is expected to be completed in February 2019, with installation and commissioning of new equipment to be phased throughout the year. The 15,000-ft

 expansion of the facility, acquired by Catalent in October 2017, will include five new packaging suites and a new quality control laboratory, creating approximately 36 new jobs at the site. 

	New equipment will include both a semi-automated and fully-automated top loading cartoner, an accessorized combination syringe assembly machine, an automated auto-injector assembly machine, and two semi-automatic visual inspection machines.

On Jan. 7, 2019, Fujifilm announced plans to invest approximately JPY 10 billion (approximately US$90 million) to expand its biopharmaceutical contract development and manufacturing organization (CDMO) business, Fujifilm Diosynth Biotechnologies (FDB) (4).

	Investments will include the addition of 2000-L single-use cell-culture manufacturing trains, cell-culture purification suites, and new microbial recovery suites to its existing facilities in North Carolina. These additions will reportedly increase cell-culture manufacturing capacity by approximately 25% and microbial capacity by approximately 50% at its North Carolina location. The company expects that the increased production capacity will be ready for cGMP manufacture by early 2020.

PCI Pharma Services (PCI), a provider of outsourced drug manufacturing, clinical trial services, and commercial packaging to the global biopharmaceutical industry, announced in a Feb. 5, 2019 press release that it plans to expand its bottling-line capacity at its commercial packaging site in Rockford, IL (5). The expansion will enable filling of an additional 100 million bottles per year at the site. Construction of the additional packaging suites began in March 2018 to add footprint for primary and secondary packaging operations equipped with high-speed tablet filling, cartoning, in-line serialization, and aggregation in support of increased customer demand. 

	PCI’s investment at the Rockford location is the latest in a series of capacity expansion initiatives across its worldwide network, including multiple facility enlargements, cold chain and ultra-cold storage extension, installations of additional packaging lines, and expansion of its serialization solutions. To further support its existing biotech infrastructure, PCI’s commercial packaging site in Philadelphia, PA recently announced a $20-million investment in commercial packaging, as well as expanded cold-chain capacity at numerous global locations.

Biopharmaceutical CDMO Rentschler Biopharma completed the acquisition of a manufacturing facility from an affiliate of Shire the company announced in a Jan. 3, 2019 press release (6).

	Under the terms of the agreement, Rentschler Biopharma will continue to manufacture for Shire at the site. The 93,000-ft

site is Rentschler Biopharma’s first manufacturing facility in the United States, located near Boston in Milford, MA with approximately 70 employees.

	“The acquisition of this modern facility fits perfectly with our strategy to further strengthen and secure our world-class CDMO position in a growing and changing market,” said Frank Mathias, CEO of Rentschler Biopharma, in the press release. “The US is a key market for Rentschler Biopharma, and this site gives us a firm foothold in this important area of growth, enabling us to better meet our clients’ needs.”

	“We will continue to make investments in our business to ensure we have the advanced technologies to remain an innovation leader in the field and the capacity to remain competitive and grow with our clients,” added Dr. Ralf Otto, COO of Rentschler Biopharma, in the release. “This includes future plans to qualify the Milford site as a multi-product manufacturing facility.”

. Cambrex, a provider of generic APIs, small molecule, and finished dosage form products and services, announced that it completed the $252-million acquisition of Avista Pharma Solutions, a contract development, manufacturing, and testing organization, from Ampersand Capital Partners on Jan. 3, 2019 (7).

	The transaction, announced in November 2018, strengthens Cambrex’s position as a small-molecule CDMO across the entire drug lifecycle, the company reports. Avista’s four sites in Durham, NC; Longmont, CO; Agawam, MA; and Edinburgh, Scotland, UK will be integrated into Cambrex’s global network, as well as its service offerings ranging from API and drug product development and cGMP manufacturing to stand-alone analytical, microbiology testing, and solid-state sciences. Cambrex now operates a total of 12 facilities worldwide and employs approximately 2000 people. This acquisition complements Cambrex’s acquisition of Halo Pharma in September 2018, which added formulation development and finished dosage manufacturing capabilities to Cambrex’s existing global API manufacturing network.

	“Acquiring Avista adds a full complement of early stage development capabilities to Cambrex’s larger scale capabilities for both APIs and finished dosage forms,” said Steve Klosk, president and CEO of Cambrex, in a company press release. “We are excited to start off 2019 integrating Avista into Cambrex’s global network of facilities. Adding Avista today and Halo Pharma in September significantly increases our customer base and funnel of projects, provides significant cross-selling opportunities and allows us to offer an integrated service offering for most small molecules from the pre-clinical stage through the commercial stage.”

	1. MedPharm, “MedPharm Announces Expansion of US Center of Excellence,” Press Release, Jan. 11, 2019.
	2. Catalent, “Catalent Invests $200 Million To Expand Biologics Capacity and Capabilities,” Press Release, Jan. 7, 2019.
	3. Catalent, “Catalent Invests $14 Million to Expand Biologics Packaging Capabilities Following Twentieth Commercial Drug Approval at Bloomington, Indiana Site,” Press Release, Dec. 3, 2018.
	4 . Fujifilm, “Fujifilm to Invest 10 Billion Yen in its Bio CDMO Business,” Press Release, Jan. 7, 2019.
	5. PCI Pharma Services, “Bottling Line Expansion to Support Customer Needs,” Press Release, Feb. 8, 2019.
	6. Rentschler Biopharma, “Rentschler Biopharma Completes Acquisition of US Manufacturing Site,” Press Release, Jan. 3, 2019.
	7. Cambrex, “Cambrex Completes Acquisition of Avista Pharma Solutions,” Press Release, Jan. 2, 2019.

	When referring to this article, please cite it as A. Lowry, “CMO Expansions and Investments," 

Suppliers set the tone for 2019 with strategic expansions, investments, and acquisitions.

CMO Expansions and Investments

Client–vendor relationships require a level of trust, open communication, and reliable deliverables. Pharmaceutical Technology spoke with Chris Mooney, senior quality assurance technical specialist at Fujifilm Diosynth Biotechnologies, a contract development and manufacturing organization (CDMO) specializing in cell culture, fermentation, and viral vectors; and Knut Niss, chief technology officer of Mustang Bio, a US-based clinical-stage biopharmaceutical specializing in chimeric-antigen-receptor-engineered T cell (CAR T) immunotherapies and gene therapies, to discuss current best practices that help ensure that quality control is maintained during the course of the client–vendor relationship. Mooney gives his views from the perspective of a CDMO dealing with materials suppliers, and Niss discusses his experience from the perspective of a biopharma company working with contract service providers as well as material suppliers.

 What criteria are sought after in a vendor/service provider?

 Here at Fujifilm Diosynth Biotechnologies, we categorize our raw materials and components. The category of the material will determine the supplier requirements. The quality tools we primarily utilize are onsite supplier audits and audit questionnaires, plus supplier quality agreements. In order to become approved, suppliers must meet our acceptance criteria. Again, the material category will determine the frequency at which each supplier is re-evaluated.

 The number one criterion for us in vendor selection is quality. We expect vendors to provide a quality system that is up to our own standards. While we are only in early stages of development, we realize that having a strong quality system is critical for an expedited path through development. We do not want to find ourselves in a situation where we have exciting clinical data with great promises for patients and then have to slow down development in order to develop appropriate quality management at the vendor. This includes the ability of the vendor to safely provide materials/services on time.

 What systems or best-practice procedures are typically in place to ensure that there is quality control/quality oversight between vendors and their clients?

A look at some best practices to ensure that quality control is maintained in the client–vendor relationship.

Pharmaceutical Technology-02-01-2019