Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

	FDA Commissioner Scott Gottlieb has been promoting drug market competition in recent months that includes new guidance documents and targeted advisories to support R&D of complex drugs and combination products. A revised draft guidance discusses studies to evaluate the adhesive performance of proposed generic transdermal and topical delivery systems (TDS) products. A second guidance discusses studies to evaluate 

skin irritation and sensitization potential of such treatments. FDA also has issued 235 product-specific guidance documents on the appropriate methods for developing specific generic TDS products (1).

	In Europe, the European Medicines Agency (EMA) has pharmaceutical companies concerned after the agency announced it was slowing down work on certain guidelines due to Brexit. The industry has been waiting for a guideline on the assessment of device components in combination products under the European Union’s Medical Devices Regulation (MDR), which requires drug-device components in integral drug-device combinations (DDCs) to be evaluated by notified bodies. The process for this is still unclear, and some companies are worried this guideline delay will affect marketing authorization of integral DDCs, which range from pre-filled syringes to complex electro-mechanical devices (2).  

	EMA, however, has assured industry that work on the MDR guideline will continue. In an interview with 

, an agency spokesperson stated: “EMA is aware of the concerns raised by the industry that came with the introduction of the new MDR, and in particular with Article 117 (requiring an NB opinion on combination products) … Work on seven guidelines which address either an urgent public/animal health need or are necessary to support and facilitate preparation for Brexit or the implementation of new or revised legislation will continue beyond Nov. 1, 2018. This includes the guideline on quality requirements of medicinal products containing a device component for delivery or use of the medical product” (2).

	1. J. Wechsler, “FDA Promotes Complex Generics and Combination Products,” 

www.pharmtech.com/fda-promotes-complex-generics-and-combination-products-0


	Vol. 42, No. 12
	December 2018
	Pages: 39

	When referring to this article, please cite it as S. Haigney, “Regulatory Developments in Combination Products," 

Articles

FDA Commissioner Scott Gottlieb has been promoting drug market competition in recent months that includes new guidance documents and targeted advisories to support R&D of complex drugs and combination products. 

Regulatory Developments in Combination Products

 An abbreviated version of this article appeard in the October 2018 print issues of 

	An API’s physiochemical properties and its pharmacokinetic profile, as well as patient considerations, should dictate drug product formulation, according to experts at Catalent. Budget and timeline constraints, however, sometimes create difficulties. “The positive effects of formulation approaches on solubility, permeability, and ultimately bioavailability should be weighed against complexity, cost, and risk-to-launch of the chosen technology,” says experts at Catalent. “It is unrealistic to expect any formulation group to tackle all these considerations without the experience from many multiple product launches or the ability to leverage the expertise across a large and diverse formulation team.”

	According to Joe Masi, Sr. Director MS&T, at Cambrex, pharmaceutical companies turn to contract development and manufacturing organizations (CDMOs) to “resolve capacity shortages, tighten development timelines, reduce processing costs, and/or lack of internal development capability, etc.” Pharmaceutical companies are requesting end-to-end services more and more, according to Masi. “This includes API, formulation development, analytical methods development, manufacturing, and packaging development. In addition, pediatric formulation and fixed-dose combination products (two or more active ingredients in one product), as well as modified-and controlled-release complex formulation, continue to gain popularity and are often outsourced.”

	When it comes to outsourcing formulation development, however, challenges may arise when scaling up from small-scale batch to commercial production. Dr. Baerbel Hinneburg, director Technology and Process Transfer at Vetter Pharma-Fertigung GmbH & Co. KG, states that “concrete planning of execution with attention to detail is critical.”

spoke with Masi, Hinneburg, and experts at Catalent about the formulation and development issues that should be considered when addressing scale-up from small-scale batches to commercial production.

	Moving from clinical to commercial phases

What formulation challenges occur when moving from clinical to commercial phases?

 From a processing and technical point of view, one example is a change in material and equipment that may occur when moving from clinical to commercial manufacturing, such as the use of larger compounding equipment or a change from disposable to non-disposable material. One must be aware of the impact a change in material could have on the relevant attributes derived from the drug product profile. This awareness avoids further lab trials that need to be undertaken to determine the appropriate operational parameters that help maintain the quality and functionality of the drug product producedwith the new process.

 Usually, batch size and equipment used throughout development phases are small due to API availability, manufacturing cost, and the scale needed to meet clinical and registration requirements. However, some manufacturing process parameters may need to be changed when scaling up or using large-sized equipment for commercial production.

	Common challenges could occur during different manufacturing steps. A few examples are listed below.

	Blending step: Material flow (i.e., the flowability of granules) is one common challenge during manufacturing. Funnel flow is non-uniform, and the materials adhere to the walls of the hopper, resulting in blend uniformity issues during the blend. To overcome the issue, change the geometry of mixers, blenders, and hoppers to improve flow of materials through the hopper. Another way is using vibratory mechanisms to ensure a mass flow or having a paddle stirrer in the hopper.

	Compression step: Sticking and capping issues are commonly observed during compression. When different compression machines are used, they may not directly generate expected results. Modification of a tableting process can sometimes reduce or eliminate film formation or sticking during compression without making any drug formulation changes. Modifications include changes to pre-compression force, compression force, and tableting turret dwell time/speed. These modifications may be helpful in delaying the sticking behavior.

	Coating step: When using a large-sized coater, some of the parameters from the small coater may not work and coating uniformity may suffer. Coating variability usually increases at a faster pace with higher pan speeds. Therefore, the first consideration is to reduce coating pace to obtain better coating uniformity. The spray distribution across the tablet bed may be another cause of the coating uniformity issue. However, with functional coatings it is important that each nozzle is spraying the same amount of coating suspension. Each nozzle must have an even spray and be calibrated to ensure it functions properly. In early formulation and clinical phases of development, there are options to modify the qualitative formulation to overcome these challenges. However, because it is often difficult to make major changes at later phase without regulatory involvement, engage with an experienced CDMO from the earlier clinical development phase. They can help to develop and manufacture quality products with minimal to no clinical or regulatory impact.

 The main challenge of a formulation proven as safe and effective for the therapeutic action tested in patients is to ensure that as we move from the beginning of the quality-by-design (QbD) process to commercial process validation, there are no changes in correlated critical material attributes (CMAs) (APIs, excipients, synthesis route, suppliers, etc.) and that none of the critical process parameters (CPPs) (associated with scale up to commercial batches) will affect the critical quality attributes (CQA) of the product that ensured efficacy and safety in clinical-phase stages. If any change is necessary to apply as part of the process, a risk assessment and mitigation should be implemented to assure the desired quality, considering the safety and efficacy of the pharmaceutical form.

	Critical quality attributes and critical process parameters

What steps should be taken for successful scale-up from small-scale batches to commercial production?

 To prepare a robust and reproducible commercial production process, we perform a QbD approach. This approach involves a combination of gap and risk analysis to identify and evaluate any factors that could potentially impact CQA and any not obvious scale-up process steps that become CPPs. A comprehensive process design to accommodate both known and newly identified CPPs, combined with a process qualification to verify a constant product quality and define a control strategy, is essential.

 First, define the target product profile (TPP), which describes the use, safety, and efficacy of the product. Prior knowledge and in-depth understanding of formulation, excipients, and process is advantageous when defining the TPP and will reduce the number of experiments and analytical testing required and, consequently, the manufacturing and testing costs.

	The next step is to identify the CQAs of the final product. CQAs should be studied thoroughly and controlled to meet the TPP. To achieve the desirable CQAs, it is necessary to identify and control CPPs. CPPs identified throughout the development and scale-up process include raw material and API controls (particle size distribution, polymorphs, and impurities), process controls, and design spaces around individual or multiple unit operations (granulation, compression, coating, packaging). These CPPs are monitored throughout development and updated upon the collection of new information.

	Successful scale up can be achieved by a QbD approach, which includes design of experiments (DoE), risk assessment, and process analytical technology (PAT).

 Most frequently, there will be changes between the equipment used in small-scale batches to ones in the commercial setting. With the difference in the equipment, the CQAs (e.g., dissolution) of the drug product could be affected, and this may depend on the complexity of the formulation. It is important to understand the correlations between the equipment scale, CPPs, and CQAs as this knowledge will help to fine tune the CPPs in the commercial-scale production that will produce drug product with the desired CQAs. These relationships can be studied by appropriate DoE at small-scale.

 How can quality by design be used to ensure quality during formulation development?

 The concept of QbD is to deliver a quality pharmaceutical product by designing a robust manufacturing process.

	Quality cannot be tested into the product at the end; it should be built into the product from the beginning. The knowledge gained from development studies can be utilized to design the working space, specifications, and manufacturing controls. Changes in formulation and manufacturing processes during development can be used to gain knowledge and support design space.

	Pharmaceutical QbD is a systematic approach with predefined objectives and emphasizes product- and process-understanding and control based on scientific knowledge and quality risk management.

	Successful QbD involves defining the target product profile and then identifying critical quality attributes, followed by developing and controlling critical process parameters etc., which will eventually ensure quality products.

	Solid QbD during formulation development can: reduce batch-to-batch variability and defects, improve product development and manufacturing efficiency, develop a robust manufacturing process that leads to greater regulatory confidence and increased product quality, improve yields, reduce investigations and testing, and lower manufacturing costs.

 Practicing QbD in formulation development emphasizes holistic and systematic investigation, understanding, and prediction of variances caused by the drug substance(s), functional excipients, formulation design, biopharmaceutics, and process development (instead of finding them out through normal means or through accidental variation). The key elements of QbD are risk assessment, conducted by cross functional teams; DoE; statistical analysis; and PAT. These elements help identify and measure risks and variabilities, correlate CMAs and CPPs to CQAs, establishing design space, control strategies, and relevant specifications, and ensuring right-first-time production at reduced costs, reduced time, and increased efficiency.

 How do analytical methods change from clinical development to commercial production?

 Often, analytic methods do not change dramatically from clinical development to commercial production, but the understanding of the method and information changes. Early phase methods are developed for speed and to minimize cost, and the assay/purity methods are commonly adapted from the method developed by the API manufacturer (for ease of tracking API impurities).

	Dissolution methods may simply be discriminating rather than profile generating, and things such as extraction procedures may need to be optimized. Once a drug has moved from clinical to commercial, a commercial quality control laboratory performs a method evaluation and transfer to confirm that the method can be performed, and the same results can be obtained using similar instrumentation. If there are any nuances to the method (understanding its variability, the level of validation performed, the experience on different equipment or by different analysts), then changes are usually minor adjustments and the method is updated. Changes in the analytical methods could support certain adjustments during a validated-state maintenance process if they merit it. Historical data generated by the method can be used to adjust or refine the acceptance criteria as the program progresses from clinical to commercial batch production.

	It is key to use these data to assess critical method parameters that must be controlled carefully as part of the overall analytical control strategy-as the molecule moves to commercial testing and release.

	Statistical tools are valuable to set acceptance appropriately for commercial products-while also considering practicality, so as to not fail a batch unnecessarily.

When moving from clinical-scale production to commercial production, what validation steps must be performed?

 The successful transfer of a product from clinical- to commercial-scale production is based on a thorough understanding of the manufacturing process, the inherent variability in the process, and strategies to mitigate or control these sources of variability.

	This knowledge is gained through scientifically based process development work and documented in reports that are used as the source documentation to create the commercial validation plan.

	The validation plan and process risk assessments are used to justify and implement the validation strategy, number of validations batches to be executed, sampling plans, and testing criteria.

	The validation batches are executed under protocol by trained personnel using qualified equipment. Enhanced physical and analytical testing may be done to assure process robustness and control. A validation summary report including physical and analytical batch data, statistical data treatment, and summary of batch outcomes is approved by discipline subject matter experts and the quality unit prior to commercial batch release to distribution.

 A total of three consecutive, successful (commercial-scale) batches need to be manufactured within 10 times the size of the registered batch size. Validation demonstrates that a specific process will produce batches that meet specification and that normal variation would not predict an out-of-specification result. Emphasis is given to those elements that have been established, through QbD, as having a significant impact upon product quality, accompanied by increased testing of samples from throughout the process. It is not good practice to use validation batches for experimentation beyond that which has already been demonstrated, as the costs of validation batches are typically very high.

What are some best practices for successful tech transfer?

 In our experience, a dedicated transfer team that includes a wide breadth of experts is crucial. This team is responsible for the process design required to perform a QbD-driven tech transfer. Roles and responsibilities must be agreed upon, and a system that enables adequate communication and feedback should be established. Open communication and exchange of all information gained during development is a key element. The license holder should also check early in the process that all partners and suppliers can provide adequate quality and documentation systems that help ascertain regulatory requirements are being met.

 The main goal of tech transfer is to transfer the product and process with minimal or no changes, which will minimize regulatory challenges and smooth the path to regulatory approval.

	The success of a technology transfer depends on several things: the quality of the finished product, open communication between two parties, feasibility of scale-up to desired levels, and compatibility of equipment at the transferred site. Therefore, it is advisable to consult with the technical and regulatory experts from the transferred site regarding the feasibility of the process with minimal impact on finished product.

	Important actions to take for a successful tech transfer include:

	• Obtain detailed technology transfer documents such as product development reports, batch records, protocols, and documents containing CPPs, CQAs, and TPPs from the transferring site. Better communication between transferring and transferred site is a key for successful tech transfer.

	• Understand formulation, manufacturing process, key equipment, function of each and every excipient, specifications, and critical manufacturing process parameters etc. for the tech transfer product.

	• Perform a gap analysis between sites (transferring and transferred site) by evaluating the equipment and supporting the information by comparing differences in the make, model, type, and capabilities of equipment available between transferring and transferred site.

	• Identify the regulatory strategy; SUPAC guidelines describe equipment in detail and classifies changes in three levels: Level I, Level II, and Level III changes. CBE30, PAS, and annual reportable are common strategies for tech transfer, which can save companies significant time and money.

	• Perform feasibility batches and capture the critical process parameters and optimize the process before registration/validation batches.

	• Gather stability data including bulk hold data on finished product to gain more confidence on the quality of the product from transferred site.

	• Generate a comparison report to compare equipment and manufacturing process parameters between transferring and transferred site and to perform a risk assessment.

 First, understand and capture the historical technical details or lessons learned from previous manufacturer (s) via discussions or detailed development reports.

	Second, understand customers’ timelines for milestones and plan critical activities (e.g., raw materials, specifications, analytical method transfer/validation, and ancillary equipment parts) accordingly.


	Vol. 42, No. 10
	October 2018
	Pages: 68–70

	When referring to this article, please cite it as S. Haigney, “Outsourcing Development: Small-Scale to Commercial," 

Industry experts discuss the formulation and development issues that should be considered when addressing scale up from small-scale batches to commercial production.

Outsourcing Development: Small-Scale to Commercial

 spoke with Aled Jones, senior product and applications manager at ProZyme; Philip Widdowson, European Application Development Scientist at Thermo Fisher Scientific; and Daryl Fernandes, chief executive at Ludger Ltd about the challenges of performing glycan analysis and how outsourcing companies can offer specific expertise.

What are the specific challenges associated with glycan analysis?

Thorough drug glycosylation analysis would involve full structural characterization of the oligosaccharides of each unique glycoform as well their absolute quantitation. However, this is not straightforward and getting even close to this still requires significant time, resources, and skill. To achieve this ideal you would, in principle, need to isolate each glycoform (including nonglycosylated drug variants), determine its relative abundance, then elucidate the glycan structures at each glycosylation site. However, it’s generally very difficult to separate out all of a drug’s glycoforms with complete resolution, and even if you have isolated a single glycoform, you need to deal with the glycans.

	At first glance, glycans look like they should be simple to analyze because they’re small molecules with a relatively small number of constituent monomers.

	However, unlike polymerization of monomers in linear macromolecules, there are many ways to link monosaccharides together to form glycan moieties. So, for each glycosidic linkage, you need to determine the identities of the connected monosaccharides, the anomericity (i.e., the special configuration) of that bond, and which of the hydroxyl groups around the monosaccharide rings are involved in the linkage.

	Also, most drug glycans are not linear structures but are branched. This means you can find glycans with identical masses and monosaccharide constituents but different topologies, and these topological isomers can confer different physicochemical and biological properties to the drug. Another problem is skewing of glycoform profiles. This can be caused by degradation of glycans or either selective losses or enrichment of glycan species during sample preparation.

	A further issue is that underivatized glycans can be difficult to visualize at analytical scale. They don’t have natural fluorophores or strong chromophores for HPCL [high-performance liquid chromatography], and their ionization on MS [mass spectrometry] can be challenging as the glycan signals are readily attenuated by other chemicals such as salts and peptides.

As glycan analysis is still somewhat of a niche, it’s perhaps less accessible than genomics or proteomics.

	Glycans display a broad structural diversity based on monosaccharide composition, linkage type, and branching. Added to this complexity is the site of glycan attachment; there is usually just one Nglycan site in the case of most IgG-based therapeutics but there can be more in Fc fusion proteins and other glycosylated biotherapeutics, and O-glycans may also be present in these.

Due to the nature of their production, glycoproteins

	are highly heterogeneous molecules with numerous different glycan structures present at a single glycosylation site (1). Glycans are commonly released from the protein prior to analysis; however, the chemical properties of glycans make them difficult to analyze in their native form.

	Therefore, glycans are required to be derivatized in order to make them amendable for traditional analytical methodologies (2). O-glycans are much more difficult to analyze in the released form due to the lack of a universal release enzyme (3). In addition, glycans can be isomeric in composition, which complicates the accurate determination of structure, particularly when using methods such as mass spectrometry (4).

What are the various methods for glycan analysis?

Glycan analysis can be approached on a few different levels, from intact protein through to glycopeptides, released glycans, right down to individual monosaccharide components. Each of these techniques have their advantages and drawbacks. The route taken may depend on the molecule and the data required, but in general, relative quantitation of released glycans labelled with a fluorophore and separated by liquid chromatography is one of the most common approaches for analysis of mAb [monoclonal antibody] Nglycosylation.

Depending on the specific information required, glycosylation analysis can be performed on different levels. Intact glycoprotein analysis allows for a quick overview of glycan distribution to be carried out. Analysis at the glycopeptide level makes site-specific glycosylation profiling possible by assigning specific glycan structures to distinct glycosylation sites.

	Analysis of released glycans analysis is currently the preferred strategy due to the high amount of information regarding the total glycan population, which can be elucidated (2). For released and fluorescently labeled glycans, HILIC [hydrophilic interaction liquid] chromatography is commonly applied either in isolation for relative quantification through fluorescent detection or coupled to mass spectrometry for characterization. More recently, there is a drive in the direction of analysis at the glycopeptide level, specifically when assessed as part of a multi-attribute method (MAM) workflow (5).

The key is to develop a glycoanalysis toolset composed of orthogonal techniques that reliably measure the glycosylation critical quality attributes (GCQAs) for your therapeutic. You need several methods because there isn’t a single technique that can cover all glycan analysis needs. In particular, you must have reliable methods for characterizing and quantifying potentially immunogenic glycans (such as those bearing Gal-alpha–1,3Gal motifs), as well as those for glycans that confer high therapeutic activity for your drug. So, selection of glycan analysis methods must be driven by a thorough understanding of the glycan structure-protein activity relationships for your therapeutic.

	Also, your toolbox must furnish the breadth, structural detail, and sensitivity needed for every stage of your drug’s lifecycle-and at suitable cost and throughput.

	This allows you to tune the methods according to the task. For example, glycan analysis for selection of clones to match your quality target product profile (QTPP) or in QbD [quality-by-design] studies to determine design space (DS) will typically require a very different performance profile from those needed for batch release.

What are the benefits of outsourcing glycan analysis for sponsor companies?

There is no single method that permits complete glycan analysis, and therefore, a panel of methodologies is often required not only to fully characterize the glycans, but also to meet regulatory requirements. Meeting these requirements in full demands the use of numerous types of instrumentation and analytical platforms. Sponsor companies regularly do not have direct access to all of these platforms, and it is not often economically or logistically viable to bring them on-site. Dedicated outsourcing companies for glycan analysis, therefore, play a key role in filling any potential gaps which may exist with respect to instrumentation and necessary expertise required to perform these methods (6).

Smaller or early-stage companies may not have the personnel to perform glycan analysis, or the instrumentation required such as liquid chromatography with fluorescence detection, capillary electrophoresis, and mass spectrometry.

	The existing instrumentation they have may not provide the data quality or capabilities of the ‘latest and greatest’.

	Or there simply may not be time to implement or run an analytical method for glycans within the constraints of a project timeline. In these cases, it can make sense for sponsors to seek an outsourcing partner that has experience with glycan analysis and can turn data around in a timely manner.

Outsourcing glycan analysis can allow sponsors to significantly extend their capabilities for drug realization. However, for success, it needs to be well-planned with a carefully chosen outsourcing partner. When poorly done, outsourcing can result in you losing time, money, and control of a critical part of your drug’s development and give you data that’s less than useful. Good outsourcing with an accomplished partner does the opposite, allowing you to overcome regulatory hurdles more smoothly and get your product to market faster than if you relied solely on your own resources.

	The first step to successful outsourcing is choosing a reliable partner with the expertise and services that match your needs.

	They need to demonstrate their ability and experience with therapeutics of similar or greater complexity to your drug. Other key considerations include the quality of communication between you and your outsourcing partner, whether or not they will share their detailed methods with you and what follow-on services they could provide. Not that reliable glycan analysis will typically be much more complex and therefore more costly than, for example, routine peptide analyses. However, with a suitable outsourcing partner and carefully considered and well-executed plan, you should benefit from a significant return on your investment.

	1. H. J. An, J. Froehlich, and C. B. Lebrilla, 

 13(4); 421-426 (2009).
	2. G. C. M. Vreeker and M. Wuhrer, 

 409; 359-378 (2017).
	3. P. H. Jensen, D. Kolarich, N.H. and Packer, 

, 277(1); 84-94 (2009).
	4. L. Veillon, et al., 

, 38(17); 2100-2114 (2017).
	5. R. S. Rogers, R. S., et al., 

, 7(5); 881-890 (2015).
	6. A. Buvailo, A. “Pharma R&D Outsourcing Is On The Rise,” 

Considering the challenging nature of performing glycan analysis, what are the benefits of outsourcing glycan analysis for sponsor companies?

Glycan Analysis: Challenges and Benefits of Outsourcing

	3. P. H. Jensen, D. Kolarich, N.H. and Packer, 

	6. A. Buvailo, A. “Pharma R&D Outsourcing Is On The Rise,” 


	Vol. 42, No. 8
	August 2018
	Pages: 56-57

	When refererring to this article, please cite it as S. Haigney, "Outsourcing Glycan Analysis," 

Industry experts discuss the challenges of performing glycan analysis and how companies can gain specific expertise from outsourcing partners.

Outsourcing Glycan Analysis

spoke with Sharon Ayd, executive vice-president of Pre-approval Pharmaceuticals and chief scientific officer at Regulatory Compliance Associates, about developing a corrective action and preventive action (CAPA) plan.

 What are the best practices for developing a detailed CAPA?

 A CAPA program requires a well-documented system that determines the root cause of nonconformances, system failures, or process problems, corrects them, and prevents them from recurring. A corrective action is a reaction to a situation that has occurred and is intended to fix the problem or modify the quality system so that reoccurrence is prevented. The result is a complete documented investigation/solution that meets regulatory requirements and is the basis for effective continuous improvement. A preventive action is initiated to stop a problem from occurring. It assumes that monitoring and controls are in place to assure problems are identified and eliminated before they happen. If the quality system indicates a problem may develop, a preventive action should be implemented to avert the situation.

 A variety of recent FDA warning letters have cited companies for not providing the agency with ‘timely’ and/or complete CAPA plans in response to FDA 483s. What does the agency consider ‘timely’? Is there a time limit CAPAs should be performed by?

 Response to a [FDA] warning letter should be done by writing a cover letter, and all observations need to be addressed as separate CAPAs. An appropriate sense of the urgency means your response should be received within 15 business days. It is advised to use the company’s CAPA form and cover letter instead of memo. The response should include documentation of the investigation with a concisely stated root cause. Containment measures and corrections for each specific observation and identified corrective actions planned with date(s) for completion also need to be included. In addition, documentation of all containment and corrective actions that are completed at the time you submit the response should be included.

How should companies develop a CAPA in response to an FDA 483?

 FDA will look for and review a company’s response. The investigator will get a copy of the FDA 483 response and will comment. As to whether the response is adequate or not will require additional review. If you don’t hear back from FDA, don’t assume the response was adequate. You should also follow-up within four to six months with a letter that includes evidence of the completed corrective actions and verification of effectiveness.

If the agency feels the CAPA is ‘incomplete,’ how should a company respond to a CAPA plan request after a warning letter?

If FDA requests or proposes additional actions or asks for a more appropriate CAPA, this means FDA is concerned with the company’s first response. The proposed actions of the company were insufficient to correct the issues cited. Presumably the company has retained a qualified and experienced third-party firm to provide guidance and if not, it is highly recommended to do so. The role of the third-party is to objectively review a company’s response to ensure it addresses all cited issues and can be implemented within an acceptable time to FDA.

 How does a CAPA plan written in response to a request from FDA differ from an internal CAPA plan?

 A company may consider their existing CAPA plan to be adequate until circumstances demonstrate that it is not. This may occur as the result of different situations that cause the weaknesses of a CAPA plan to rise to FDA’s attention. Perhaps there are numerous consumer complaints, recalls, or an FDA inspection that is the impetus that uncovers deficiencies or failures in a company’s CAPA plan. Regardless of the reason, it is expected that FDA will request a company to address every issue associated with their CAPA plan and to understand what changes are needed and to implement them.

Pharmaceutical Technology spoke with Sharon Ayd, executive vice-president of Pre-approval Pharmaceuticals and chief scientific officer at Regulatory Compliance Associates, about developing a corrective action and preventive action (CAPA) plan.

Responding to FDA CAPA Requests (2018)

Good manufacturing practices (GMPs) are established by regulators to ensure that pharmaceuticals are safe and effective for the patients that rely on them. In the United States, requirements governing finished pharmaceutical quality are described in the Current Good Manufacturing Practices (CGMPs) regulations established by FDA and published in the 

, parts 210–211 for most finished pharmaceuticals). FDA also publishes guidance to further describe recommended practices for complying with the CGMP regulations. The agency states that “CGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations” (1).

	In Europe, GMPs are defined by the European Commission in 

–Volume 4–Good Manufacturing Practice (GMP) guidelines (2), which were first published in 1989. EudraLex states that quality management is “a system of marketing authorizations [that] ensures that all medicinal products are assessed by a competent authority to ensure compliance with contemporary requirements of safety, quality, and efficacy” (2).

	To harmonize GMPs and other quality requirements worldwide, the International Council for Harmonization (ICH) works with international regulators and industry to develop common guidelines across the industry to ensure consistent quality expectations worldwide.

	“At its core, CGMP is a science- and risk-based focus on assuring drug quality. As described in ICH Q10, 

, an overall attitude to drive meaningful and continuous improvements from the quality unit and other manufacturing employees is essential” (3), FDA told 

	The global nature of the pharmaceutical supply chain requires regulatory agencies to inspect and govern GMPs at manufacturing facilities. These inspections sometimes result in actions by regulators (e.g., FDA 483s, warning letters, import bans, and court actions) against companies that fail to follow GMPs. Common CGMP deficiencies cited by FDA in warning letters sent to pharmaceutical companies inspected during the past year include failures to ensure product sterility, ensure data integrity, create quality control units, and develop and follow written procedures (4–7).

	“Companies should vigilantly encourage manufacturing practices that reflect the most current and robust methods of processing and control, and with a focus on providing a quality product to US consumers,” says FDA. “The approach to successful CGMP is not merely a check-box approach where a single obstacle can be identified, nor is it meant to be unchanged throughout the life of a product or a facility. Using a holistic and quality risk management approach, a manufacturer can select and study specific products and processes with the goal of continual improvement of product quality and quality systems and widespread optimization.”

	So how do companies ensure they are “vigilantly” following GMPs and avoid the wrath of regulators? The answer appears to be found in a company’s “quality culture” and in the development, writing, and following of written procedures.

	Performing pharmaceutical manufacturing according to GMPs involves a dedication to quality throughout development and manufacturing processes. “Corporate management plays a vital role in this endeavor by establishing a commitment to quality, which includes providing sufficient resources and oversight for manufacturing operations. There are many elements to successful implementation of CGMPs but measuring and monitoring quality indicators and managing change are key among them,” says FDA.

	According to Susan Schniepp, executive vice-president of Post-approval Pharmaceuticals and distinguished fellow at Regulatory Compliance Associates, maintaining GMPs throughout all processes and procedures involves a combination of personnel training, keeping tools and equipment updated, having a strong quality unit, and developing a quality culture at all levels of the company. “How the company goes about achieving this objective is what is critical. Traditional training may not be enough. There should be constant on-the-job training and oversight on a continual basis. Upgrading tools and equipment, especially computer-driven programs, needs to involve IT departments and adhere to the current data integrity concepts,” says Schniepp. “No one element will be able to sustain GMPs. All the elements work together to establish a culture where sustaining GMPs is a priority.”

	Chris Moreton of FinnBrit Consulting agrees. “Too often, in my experience, certain factions in an organization think that quality is someone else’s responsibility. There may be an organizational chart that shows where the quality unit sits in an organization, but ‘quality’ (including GMP) is everyone’s responsibility within an organization; from the most senior to the most junior and vice versa.” Management is key in creating a quality culture, says Moreton. “If the staff see the managers taking an interest and checking on things on a daily basis, the staff will respond, and they will try harder to get things right.”

	A commitment to staying current with regulatory expectations is a must, according to Schniepp, and she warns that complacency is the biggest obstacle to maintaining GMPs. “Once a process or procedure is established and functional, there does not seem to be the impetus to update and revise it as regulatory interpretation and understanding changes. This leaves the process or procedure compliant to outdated standards,” Schnieep says.

	Companies must also learn from prior mistakes, according to Mark Lynch, vice-president of Strategic Compliance at Parexel. “It’s best to take the lessons learned from product experience and apply them to the culture overall so those lessons only need to be learned once. Those experiences should be continuously applied on the product level, and also used to make improvements to standard operating procedures (SOPs), policies, personnel, and technology.”

	Problem solving is another technique that must be honed, according to Lynch. “Companies must also pay continuous attention to problem identification, solution, and improvement. Refinement of problem-solving techniques contributes to organizational learning.”

	Enforcing quality procedures through a policy that ties failure to follow procedures with grounds for dismissal and using internal audits to detect improper performance are options to ensuring a quality culture, according to Lynch. “It is also important that tools are a regular topic of discussion with operators to capture improvements and assure consistency. Additionally, sufficient supervisory presence and oversight are key both for monitoring purposes, and to be sure operators can raise questions and get the support they need. Finally, it’s best practice to put a reporting mechanism in place that does not require identification, so employees feel comfortable flagging an issue without fear of blame,” he says.

	Lack of consistent GMPs may lead to repeat offenses

	Companies who do not consistently maintain GMPs may find themselves under additional scrutiny by regulators for repeat offenses. A variety of FDA warning letters have pointed out repeat CGMP violations at companies and/or a particular facility (8, 9).

	FDA reports that the agency, “… strives to provide clear guidance to companies proactively and in its enforcement actions. Where repeated violations have been found at the same facility or among different facilities of the same firm, we highlight those violations so that they may be addressed adequately. A focus on a commitment to quality is essential to correcting repeated violations, as are adequate corrective actions and procedures. While we generally encourage a focus on overall quality, there are times when we encourage firms to take specific actions, which are included in our warning letters as well as in applicable guidance documents and regulations.”

	Repeated offenses may be a failure to look at the big picture and apply solutions across all systems and/or products, according to Schniepp. “Companies think in terms of solving the individual citation but fail to take that answer for change to a global look at fixing other processes and procedures that might be susceptible to the same observation. Tunnel vision when responding to warning letters has a great potential to result in repeat observations,” says Schniepp.

	“Some of these ‘repeat mistakes’ are found to be violations of the same section of the regulations but stem from a different problem. Investigators tend to use repeat findings as a way to point to simplified trends that make one issue appear to be really bad, rather than the complex combination of issues that it truly is,” Lynch says. “Some companies lack the staff, procedures, capability, and time to fully investigate and solve problems, so they pick something (e.g., a personnel error), close the investigation, and move on to release product, and the same issue reappears because it wasn’t solved.”

	Cost can be another factor to repeated offenses, according to Moreton. “Often cost and/or short-term shareholder interests are used as an excuse to avoid some measures [to long-term change] … People complain that quality costs money, but if they really want to see how expensive things can be, they should try a consent decree.”

	Developing and following written procedures

	The lack of written procedures and/or a quality unit is another frequent infraction identified in warning letters. From October 2016 through September 2017, FDA issued more than 400 FDA 483 observations for a lack of written procedures or written procedures that were not fully followed (10).

	Written procedures are key to a robust quality program, according to FDA and industry experts. FDA believes that the “most effective quality assurance (and compliance) strategies begin with robust internal procedures to adequately design and maintain a robust operation, and that can quickly identify and correct manufacturing problems when they occur.”

	What are best practices for developing written procedures for GMPs? While the agency does not endorse one particular approach to developing written quality procedures, FDA notes that these procedures should “be written to effectively communicate to the users of the procedure. FDA recommends that the style and format of procedures be accessible to users, as well as ensuring adequate coverage of its purpose. We recommend that the effectiveness of a procedural training program be evaluated to ensure that personnel learn and can follow the procedures as intended.”

	The trend in a failure to have written procedures is disturbing, according to Schniepp. She suggests that outsourcing quality, especially for start-up companies, may add to this problem. She questions whether outsourcing companies have the processes and procedures in place to handle new products. A robust sharing of information between client and contract manufacturing organization is also key, including product and process understanding. “We need to also remember that new products, particularly in the biotech segment of the industry are novel in nature so the old way of doing business may not be applicable. Whatever the reason the industry must focus effort on making sure there are processes, procedures, and written instructions in place that support the release of product,” Schniepp stresses.

	Having all parties involved in the development of written quality procedures is necessary. “Including everyone affected by the procedure and writing the procedure with their input will result in streamlined and efficient procedures, which will be easier to maintain in the long run,” says Schniepp.

	Standard operating procedures (SOPs) written by people not familiar with the specific operation can cause disconnects, according to Lynch. “The best way to assure adequate SOPs is to sit down with people most familiar with operations and map out the process steps and handoffs. This can be incorporated graphically using [swim lane diagrams] and similar tools like Visio (Microsoft) and include them as part of the document.”

	“In my opinion, in order to ensure that quality procedures are effective, it is necessary to involve those who know the process or operation being documented,” Moreton agrees. “This may mean sitting down with the operator and finding out exactly what is being done and how, not what management thinks should be done and how they think the operation(s) should be carried out.”

	According to Schniepp, procedures should be mapped out, committed to paper, reviewed periodically, and updated as necessary. “Companies need to remember that their processes and procedures are not carved in stone and need to be changed to stay compliant with the operations being performed and the current interpretation of regulations,” says Schniepp. New technologies and new product types may necessitate an update to procedures. Companies should be careful to not try and fit technology or product advances into current procedures but should instead take the time to review their processes and procedures and update them appropriately in responses to these advancements, she says.

	Consistent review of procedures is important, especially if a change in equipment, facility, or regulatory requirements has occurred, experts note. “Written procedures should be reviewed and updated as often as needed. However, if a process and procedure is being updated frequently then it probably wasn’t very well written in the first place,” says Schniepp. “This being said, procedures that are fairly stable should be reviewed at least every two years to make sure they are still current and reflective of regulatory expectations.”

	When developing written procedures, says Lynch, “each process and procedure should be tailored to its specific purpose, so they don’t include unnecessary steps that add time to the process without applicable value to the procedure at hand.”

	Companies often lack details that will help operators understand the process, says Lynch. “The most important concept to remember when writing procedures is to include the detailed instructions for the operation or processes being defined by that procedure and not include extra explanatory or extraneous information that has no bearing on the operation or process being defined,” agrees Schniepp.

	In warning letters, FDA commonly suggests the hiring of a third-party GMP consultant to help companies address their GMP deficiencies. Schniepp says these consultants can provide a “fresh perspective” when resolving GMP issues. “A new and fresh approach is valuable because the consulting firm has no preconceived ideas and can offer new insight to what may seem to be an old and uncorrectable problem,” says Schniepp. These consultants can be helpful even when not suggested by regulators “because they are looking at the quality with eyes not steeped in the corporate culture,” according to Moreton.

	Consultants also have knowledge and expertise the company does not have. “[Consultants] can offer a variety of approaches and suggestions for remediating current problems as well as offering solutions to maintain and improving systems moving forward. One of the most important aspects to consider when hiring a consulting firm is to make sure they not only have the expertise, but they also have the time to devote to fixing the problem,” says Schniepp.

	When hiring a GMP consultant, Moreton suggests companies look at the experience of the contractor as a whole as well as the qualifications of the individual consultants “to ensure there is a good fit with the contractee’s needs.”

	Lynch warns, however, that pharmaceutical companies should not rely too much on outside help. “Consultants can help companies get back on track if companies lack the resources internally. However, eventually companies have to sustain compliance themselves. Third-parties should provide expertise in the needed area and technology and have demonstrated success. Then, they should be able to teach and mentor personnel for improved behaviors and provide flexible models to fit company operations and culture. Usually, this is more than one-time training, but a program of measurement and support over time.”

Facts about the Current Good Manufacturing Practices

Warning Letter 320-18-17 sent to Deserving Health International Corp.

Warning Letter sent to Ridge Properties, LLC dba Pain Relief Naturally

Warning Letter sent to Meridian Medical Technologies, Inc., a Pfizer Company

Warning Letter 320-18-05 sent to Guangzhou Baiyunshan Pharmaceutical Holdings Co. LTD

Warning Letter 320-18-47 sent to Lijiang Yinghua Biochemical and Pharmaceutical Co., Ltd.

FY 2017 Inspectional Observation Summaries


	Vol. 42, No. 7
	July 2018
	Pages:18–23, 60

	When referring to this article, please cite it as S. Haigney, "Maintaining GMPs Requires Continued Vigilance," 

Maintaining good quality control practices throughout the entire manufacturing process requires robust development, a drive toward product and process understanding, and pre-established, comprehensive written procedures that are consistently reviewed and updated.