Jana Spes is Vice-President, Technical Operations, Apotex, jspes@apotex.com.

Jana Spes

	The continuous manufacturing  concept originated from pig iron production using a blast furnace, where the process operates for multiple years without shutdown. The approach is followed in production processes for oil refining, chemicals, synthetic fibers, fertilizers, power generation, natural gas, and waste-water treatment. The application of continuous manufacturing in pharmaceutical and biopharmaceutical manufacturing has progressed in the past decade with adoption of the same approach as leading industries. So far, some pharmaceutical products are manufactured and marketed using this concept, notably by Janssen and Vertex (1).  

	The options of an in-line process analytical testing approach for process controls and automation in processing is providing some level of semi-continuous manufacturing, resulting in reduced waste and downtime with increased gross margin and profitability. The conversion of batch processes to continuous manufacturing is the future of the pharmaceutical industry, employing the continuous flow, end-to-end integration of manufacturing sub-processes with a significant level of control strategies. The benefits of continuous manufacturing over traditional batch processes are evident, but the implementation is still at snail speed (2). The pharmaceutical industry is acknowledging continuous manufacturing as an option to improve and sustain manufacturing operations. The pharmaceutical industry is making efforts by internally assessing, developing, and implementing semi-continuous manufacturing processes to improve manufacturing efficiencies.

	For a successful integration of continuous manufacturing, an orchestrated coordination amongst several industry partners is essential. The three major components for successful implementation are equipment and process analytical tool manufacturers, API and excipient manufacturers with a focus on process controls in providing consistent supply, and the finished product manufacturing facility in developing strategies for integration of techniques for implementation. The integration of a segmented batch processing and testing to a single flow is a major task in achieving continuous operations. As such, processes have inbuilt significant lag-time between operations from start to end and delivering to patients, which can range from three to six months. The reconfiguration of equipment to control the quality of the API and excipient can improve the effective asset utilization (EAU) by having a dedicated production line for large-volume product manufacturing. To achieve such an objective, the organizational mindset, regulation, and technology balance is a challenge in the pharmaceutical industry. The success lies in achieving the concept of raw material input into the system at the beginning of the process and discharging all at once as finished product sometime afterwards. The key to this process is that the finished product has uniform characteristics throughout the processing and meets set quality standards (3).

	Regulatory challenges of continuous manufacturing

	The level of regulatory submission requirements and inconsistent requirements around the world makes it difficult for the pharmaceutical industry to make any significant changes to an approved process, as any delay results in loss of market share in a highly competitive environment. There are minimal regulations or industry guidance documents on continuous manufacturing, and nothing is prohibiting implementation (4). Regulatory agencies do recognize that continuous manufacturing is a modern manufacturing approach with the potential to improve the assurance of quality and consistency of drugs, enabling quality to be directly built into process following quality-by-design (QbD) efforts. Because a true continuous manufacturing process is not feasible, producing a finished product batch in a defined production time period based on variations due to different lots of API or excipient as input or equipment cycling capability utilizing a chain of unit operations in continuous mode is an acceptable approach. It will require a significant reconsideration of the control strategy and well-defined methods employed to assure uniform characteristics and quality within specified limits for finished products. These goals can be achieved by well-defined characterization of input materials, selection of appropriate in-process sampling frequency of testing, setting of appropriate acceptance criteria, and statistical process controls with a feedback mechanism.

	Factors in processing, such as equipment, cycling capability, and interaction of unit operations, need to be controlled. FDA supports the implementation of continuous manufacturing using a science- and risk-based approach and recommends early and frequent discussion with the agency before implementation of manufacturing technology. FDA has developed a program to help industry through its new guidance on advancement of emerging technology applications to modernize pharmaceutical manufacturing base (5). The regulatory requirement for the quality of the product remains the same as in batch processing, but for continuous manufacturing, the sampling plan needs to be redefined, deviations need to be handled differently, variability should be controlled, manufacturing changes need proper management, and the rationale for testing of a continuous batch must be defined in comparison to the traditional model (6).

	Barriers to implement continuous manufacturing

	The current manufacturing process followed by most of the pharmaceutical industry has many unit operations performed in segregated locations to form a batch and has limitations in flexibility, as the process controls are not dynamic. Performing continuous manufacturing based on QbD principles with reorganized manufacturing equipment and testing instruments and improved technical skills of the professionals who run these processes is a challenging task. The process of switching from a traditional manufacturing process stream to continuous manufacturing requires a commitment for capital investment to upgrade manufacturing equipment and install appropriate process analytical tools to control the process and develop control strategies to ensure equivalency of the two processes (6). A decision to switch to continuous manufacturing is still a big question for users as risk of cross contamination, cleaning frequency, and equipment breakdown need to be addressed to a satisfactory level. The users are concerned that not all equipment can perform continuously. For instance, tablet compression tooling is constructed with stainless-steel of different grades that are not meant for continuous use because the force applied in the process generates stress on the stainless-steel, which results in wear and tear that can affect the product physical quality attributes. The product quality expectation remains the same for continuous manufacturing as for traditional batch manufacturing. The continuous manufacturing risk assessment requires a good understanding of the process dynamics, process conditions, and material attributes to manage the risk. The continuous manufacturing process requires use of model-based control, multivariate monitoring, and large database management for analysis in real time to support real-time release testing (RTRT). The communication of residual level of risk by acquiring effective control strategy to the risk assessment for product and process development, as well as product lifecycle management, requires linking of the system for effective feedback.

	Continuous manufacturing requires an understanding of the process and dynamics impacted by interaction with process parameters and material attributes. The process dynamics require a level of controls including raw material controls, process monitoring, and detecting and handling deviation in real time to support a real-time release testing (7). The batch definition and control strategy verification should be defined up front. Process understanding of the continuous manufacturing should be established based on design space and design of experiment (DoE) at development stage. A predictive model should be built with simulation capability to define action limits and an approach to manage process deviation with adjustment of process parameters. The process dynamics controls characterized by residence time distribution help identify the failure mode or deviation and changes in set-point impacting the start-up and shut-down on material quality. For an effective control strategy to keep continuous manufacturing in a state of control, an appropriate approach for individual process and product as assessed by risk analysis is required. The control strategy should provide consistent assurance of process performance and quality and should be designed to mitigate product quality risk in response to deviation over the time of continuous manufacturing.

	Any given process uses multiple raw material lots in a batch, which require a process to establish traceability in a finished product. For a smooth, continuous manufacturing process, particle size distribution and density of raw material should be controlled such that they do not affect the flow behavior, mixing of ingredients, and dosage uniformity. The monitoring process will require the appropriate use of process analytical tools and modeling capability. The decision to select a tool should consider interference generated in testing due to flow of powder, time of data acquisition with respect to flow, and locations and number of installed probes or sensors at key sampling points. There should be a backup plan for each sensor or probe in case of failure during the process, which can affect the process monitoring and data acquisition. The acquired data are critical as they support the real-time monitoring and multivariate analysis to keep the process in a controlled state.

	The cost of replacing traditional batch manufacturing with continuous manufacturing could be a significant investment; however, it offers cost savings subsequently by reducing waste, loss of batches due to failure, cost of testing, and inventory overhead cost. It is a smart move if the pharmaceutical industry starts with a hybrid continuous manufacturing approach to keep the initial investment cost lower and start generating gains. These gains can offset the cost of equipment and instrumentation faster and provide more confidence in the newer technology. The manufacturing cost of products varies with the type of equipment used.Integrating the existing equipment on site with upgrades to achieve hybrid continuous manufacturing can be a cost-effective approach, rather than building a complete integrated system to replace existing systems. It is more appropriate to have a complete continuous manufacturing system to start in R&D environment, which gives more opportunity to master the continuous manufacturing technology to implement subsequently in a commercial environment with more success. Future manufacturing processes involving continuous manufacturing with increased processing speed and controlled and monitored quality parameters, which lowers  the cost of manufacturing, gives a distinct advantage to generic-drug manufacturers.

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry

International Symposium on Continuous Manufacturing of Pharmaceuticals: Implementation, Technology & Regulatory

Articles

The pharmaceutical industry is making efforts by internally assessing, developing, and implementing semi-continuous manufacturing processes to improve manufacturing efficiencies. 

Continuous Manufacturing: A Generic Industry Perspective

FDA’s focus on the quality culture and its request for quality metrics may ensure a successful company-CMO relationship. FDA’s draft guidance 

, Rev 1 (1) is now accessible after extensive deliberation and comments from the industry. 

 that measurements to evaluate quality of facilities and processes should aid the agency’s site inspection efforts (2). The guidance is expected to ensure that drug products are continually manufactured under high quality standards. In addition, it encourages manufacturers to self-monitor using robust quality measurements. 

	FDA recognizes the trends in current pharmaceutical business models with multiple contract manufacturing organizations (CMOs) involved in commercial manufacturing and supply-chain operations. FDA 

 (3) justify the need for clearly defining cGMP-related roles between product owners and contract facilities. The final FDA industry guidance on Contract Manufacturing Agreements for Drugs: Quality Agreements was issued in November 2016 (4).

 at a healthy rate of 7.5% annually; many of them converting from CMOs to contract development and manufacturing organizations (CDMOs) (5). FDA recognizes that CDMOs can enhance speed, efficiency, technical expertise, scale-up knowledge, and expertise (4). The guidance will ultimately benefit the patients who are prescribed drug products manufactured at the CMO sites under the agreement. Illustrative cases discussed in the guidance are typical with CMO projects. The agency considers the product owner ultimately responsible for ensuring their product, a human, veterinary, biological, biotechnology drug product, a drug substance, an in-process material or a combination product, is made in compliance to cGMPs even though a quality agreement may assign specific manufacturing activity to the CMOs. The European Union guidance also entails that outsourcing activities should be defined and a contract written to avoid misinterpretations that may result in poor quality (6). 

	International Council for Harmonization (ICH) Q10 and Pharmaceutical Inspection Co-operation Scheme (PIC/S) 

Good Manufacturing Practice for Medicinal Products

 require written agreement between contract giver and acceptor for outsourced pharmaceutical activities (7, 8). A written quality agreement is, therefore, a collective requirement in the industry, developed in consultation with a cross-functional team, ensuring partners operate with the same reference guidance (9). The collaborative development of the agreement provides a better sense of the CMO quality systems and quality focus, which will potentially pave the way to improved business relationships. Lack of clarity on cGMP responsibilities can put both product owners and contract facilities at risk. The resulting scenarios such as non-compliance, broken contracts, drug product shortage, and loss of market have a direct business impact for both parties. 

 guidance was issued in July 2015. This guidance document explained the intent of FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) to collect data and use 

 to ensure continuous improvement and innovation in the industry (10). FDA’s directors acknowledged that the guidance is an important first step on a shared industry/regulator effort toward further improving drug quality (2). Webinars and public consultations were held to communicate the key points about the guidance’s intent, namely encouraging the industry in implementing good quality management systems, improving regulators’ risk-based inspection management, and to better forecast potential for shortages in drug supply chain. FDA supplemented the draft with a technical conformance guide, providing the industry with specific technical details on the quality metric data submission requirements (11). The agency has considered 

 (12) on the first draft. The revised guidance post consultation now allows firms to report quality metrics by product or by site. FDA has also revised the requirements for data reporting and has added some examples. The initial intent is to have the reporting voluntary. One notable exclusion in the current revision is that of the Optional Metrics Related to Quality Culture and Process Capability/Performance. FDA has also incorporated a provision for firms to submit a 300-word comment to provide further explanation on the submitted data, and to elaborate on further plans for improvement. 

	The quality metrics guidance is a result of a carefully considered long-term quality improvement strategy from FDA. This guidance, as discussed in the background section, continues the efforts initiated by FDA since development of the final report on Pharmaceutical cGMPs for the 21st Century-A Risk Based Approach (13) from September 2004. The report identifies that product quality and productivity improvement share a common element (i.e., reduction of variability by virtue of process understanding though the lifecycle). It reinforces that reducing variability provides positive outcomes for both patients and the industry. 

	One reportable metric is the lot acceptance rate (LAR). This metric is an effective tool for estimating the cost of quality for manufacturing sites. It would reflect the real effectiveness of unit operations or continuous manufacturing lines, where current measurement norms focus primarily on productivity numbers. The LAR metric allows for senior management decision making and continuous improvement opportunities for products.  

	The second reportable metric is product quality complaint rate (PQCR), ensuring patient or customer focus. Regulator expectation is to ensure timely and effective corrective actions and preventive actions (CAPA) are taken when customer complaints arise. With an improved PQCR, the industry will achieve considerable patient confidence and professional goodwill, a desired outcome for any pharmaceutical organization. 

	The guidance indicates that invalidated out-of-specification rate (IOOSR) is an indicator of the laboratory operations effectiveness. This includes IOOSR from both routine release and stability testing. Analytical variability is one of the major sources of variability for test results (14, 15). Routine calculation and reporting of IOOSR will provide a threshold for further investigation into the root cause of such unintended analytical variability (e.g., analyst, instrument, test method, reagents, standards). The metric can be incorporated as part of the analytical quality by design (AQbD) continued monitoring stage (16). Commercial laboratory operations are equally critical as manufacturing operations. The index provides senior management clear insights into the true laboratory operations efficiency; highlighting the level of analyst expertise, need for instrumentation upgrades, performance of external laboratories (if any), and capturing analytical method robustness. 

	FDA intends to publish a list of establishments that voluntarily report quality metrics. By doing so, the agency would be effectively propelling industry participation in regularly reporting metrics by publicizing the efforts put in by those organizations to key stakeholders. The agency engagements during the voluntary reporting phase is an opportunity for organizations to demonstrate effectiveness of their quality management systems, product/process control strategies, and cGMP compliance. The guidance itself identifies that the list may be useful for identifying contract manufacturers and for healthcare purchasing/sourcing groups. The reporting organizations will be categorized and identified into top and mid tiers such that the stakeholders can recognize the level of data being submitted. 

	With the recent focus in quality culture and pharmaceutical quality systems by regulators, the industry is expected to ensure better quality and predictability, driving businesses to succeed. The 

Submission of Quality Metrics and Contract Manufacturing Agreements for Drugs: Quality Agreements

 guidance documents are rightly aligned with this goal. FDA may request information such as product recall and customer complains as per Section 704 of the Food, Drug, and Cosmetic (FD&C) Act (17). Also, 21 

) Part 211 (a) requires the company’s quality unit to be responsible for products manufactured by a CMO (18). The business benefits of effectively implementing the guidance requirement include prevention of manufacturing issues, prediction of supply disruptions, and development of a sustainable CMO relationship in addition to the non-tangible element of stakeholder confidence and goodwill. The new quality standard guidance’s developed by FDA will improve regulator-industry transparency. It will reduce process variability and encourage use of the best technology and innovation in the pharmaceutical industry. Adoption of guidance requirements will result in well-established quality systems through the manufacturing sites; potentially reducing the regulators resources required for monitoring (e.g., reduced site audit cycle). Both the patient and pharmaceutical companies are positioned to significantly benefit from the current regulatory strategies. 

Guidance for Industry, Submission of Quality Metrics Data, Rev 1, Draft Guidance

 (CDER, Silver Spring, MD, November 2016).
	2. A. Boam and M. Malarkey, “‘Quality Metrics’: FDA’s plan for a key set of measurements to help ensure manufactures are producing quality medications,” 

, July 2015.
	3. FDA Enforcement Actions, 

Guidance for Industry, Contract Manufacturing Agreements for Drugs: Quality Agreements

 (CDER, Silver Spring, MD, November 2016).
	5. N. Walker, 

(January 2016).
	6. European Commission, 

Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

, Volume 4, Chapter 7 (European Commission, January 2013).
	7. ICH, Q10 

Pharmaceutical Quality System, Quality Guidelines

, Part 1, Chapter 7 (PIC/S, January 2017).
	9. A. Pazhayattil, 

 (May 2008).
	10. FDA, Quality Metrics for Drug Manufacturing, cGMP’s for Drugs: Reports, Guidances and Additional Information, 

Technical Specification Document, Quality Metrics Technical Conformance Guide

Technical Specification Document, Comments-Docket ID: FDA-2012-D-1595

, FDA.
	13. FDA, Final Report, Pharmaceutical cGMPs for the 21st Century-A Risk-Based Approach (FDA, September 2004).
	14. B. Nunnally, 

 78-88 (Summer 2009).
	15. N. Sayeed-Desta, et al., “Assessment Methodology for Process Validation Lifecycle Stage 3A,” 

: 1-6 (2016).
	16. G. Martin, et al., “Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification,” USP Stimuli Article. 
	17. FDA, 

Guidance for Industry, FDA Records Access Authority Under Sections 414 and 704 of the Federal Food, Drug, & Cosmetic Act

 Chapter 1, Subchapter C, Part 211, Subpart B, Section 211.22 (a), April 2016. 


	Vol. 41, No. 2
	Supplement
	February 2017
	Pages: s40-s42

	When referring to this article, please cite it as N. Sayeed-Desta, A. Pazhayattil, and J. Spes, "Quality Metrics and CMO Agreement," Supplement to 

FDA’s focus on the quality culture and its request for quality metrics may ensure a successful company-CMO relationship.