Naheed Sayeed-Desta

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 FDA’s draft guidance 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 

Articles

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

Quality Metrics and CMO Agreement

Establishing a commercial batch size is a crucial decision in pharmaceutical operations. It is influenced by the type of manufacturing technology being used, regulatory filing commitments, supply chain demand, and operational planning factors. To understand batch size, the differences between “batch,” “continuous,” “semi-batch,” and “semi-continuous” manufacturing must first be defined (1). In batch manufacturing, all materials are charged before the start of processing and discharged at the end of processing. Examples include bin blending and lyophilization. Continuous manufacturing involves materials simultaneously charged and discharged from the process; examples are found in petroleum refining, food processing, and, more recently, in pharmaceutical manufacturing. Other manufacturing variations include semi-batch (i.e., fed-batch) manufacturing, as found in wet granulation, tablet coating, and fermentation, in which materials are added during processing and discharged at the end of processing. In semi-continuous manufacturing, materials are simultaneously charged and discharged, but for a discrete time period. Examples include roller compaction, tablet compression, and encapsulation. For semi-continuous manufacturing processes, the process output is independent of batch size as long as the material input is set up to produce consistent output as per the controlled process. Therefore, a fixed batch size is not required for semi-continuous manufacturing processes.

	Regulatory guidances provide clarity on batch requirements. FDA’s 

Guidance for Industry: Immediate Release Solid Dosage Forms Scale Up and Post Approval Changes 

(2) outlines the  maximum allowable batch size as 10 times the size of the pilot/bio batch. FDA’s cGMP guidance 

 (3) provides clarity on batch and lot definitions. A European Medicines Agency (EMA) draft guideline on manufacture of finished dosage forms (4) notes that the batch size for a product to be marketed should normally be compatible with qualified equipment. It should be sufficient enough to allow process capability to be established. For example, a commercial batch size for solid oral dosage forms should be at least 100,000 units unless justification is provided. The equipment capacity and maximum quantity allowed determines the maximum batch size.

	Operational efficiency increases with use of smaller batch sizes for such semi-continuous operations as compaction, tablet compression, and encapsulation. Taking the product out faster achieves higher asset and line capacity utilization. Having a minimum possible batch size can also increase supply chain velocity. Examples of unit operations that are not affected by having non-standard batch size include: particle size reduction, fluid-bed drying, roller compaction, extrusion, tablet compression, and encapsulation (5).

	FDA’s 2015 guidance on emerging technology (6) promotes adoption of continuous manufacturing technology, and the recent approval of tablet production on a Janssen continuous manufacturing line highlights regulators’ acceptance of continuous manufacturing, as long as product quality is maintained. Traditional tablet compression and encapsulation operations are semi-continuous manufacturing operations, which implies that the same duration for the tablet compression or encapsulation run should yield similar quality product. The following sections discuss approaches for determining and provide justification for an appropriate minimum batch size for semi-continuous dosing unit operations, such as tableting and encapsulation.

	Control strategies for tablet compression and encapsulation manufacturing include in-process quality control specifications for such quality attributes as tablet weight, hardness, thickness, friability, and disintegration time. These attributes should be measured frequently (i.e., at intervals of 15 or 30 min.) throughout the run. The quality attributes are guaranteed through the compression run by force control established during product set-up. Any tablet compressed beyond the upper and lower limits of the set main compression forces will be rejected. For both tablets and capsules, 100% or frequent weight sorting/check are also used to assure product quality over the entire run.

	Powders, however, exhibit complex behavior during processing. The internal dynamics of powder systems under dosing are specific to a product. The start and end fraction samples are considered “worst case” and are indicative of segregation issues that may occur during a routine manufacturing process. Solid-dose tablet compression/encapsulation processes do not typically include purging as a control strategy to reduce segregation risk. Therefore, along with the stratified process validation (PV) Stage 1 content uniformity data, the content uniformity results from PV Stage 2 batches provide a clear indication of homogeneity. Typically, stratified samples are collected from across the dosing run from 20 locations to verify consistency and reproducibility throughout the batch, and replicate samples are tested for uniformity per location. The unit dose is also tested to confirm product-specific physical and chemical quality attributes (see 

). In addition to content uniformity, active ingredient homogeneity is evaluated in powder blends (i.e., blend uniformity) in all products at each batch size and bin size at Stage 2. The drug-content uniformity is determined by blend uniformity, stratified dosage uniformity, and assay. In-vitro performance of the dosage form is assured by dissolution testing. Based on the assurance of multi-component uniformity and in-vitro performance, it can be concluded that a semi-continuous tablet compression/encapsulation process is capable of producing consistent unit doses with any dosing batch size.  

			Table I. Testing conducted during Stage 2 Process Performance Qualification Studies.			

					Appearance, individual tablet weight, weight of 10 tablets, hardness, thickness, friability, disintegration 

					Stratified dosage uniformity (minimum of 20 samples), assay, dissolution profile, product-specific certificate of analysis and submission requirements. 

					Appearance, individual capsule weight, weight of 10 capsules 

	In a systematic approach to determine the minimum tablet compression batch size, the following factors can be considered: tablet weight, API percentage, manufacturing process, and set-up waste from similar products and/or processes. 

 The total run time for the dosing batch is based on the target tablet/capsule weight. For any assigned minimum batch size to be compressed, the products with minimum tablet weight will take more time to compress than products with maximum tablet weight. As per the Stage 2 stratified sampling, a total of 20 locations are sampled during the dosing run. Therefore, use of a minimum batch size can be evaluated with products of low and high unit weights. 

Robustness of unit dose weight uniformity.

 Tablet weight is typically monitored using force control mechanism throughout the tablet compression process, where rejection limits (S+ and S- rejection forces and M+ and M- adjustment forces) are defined. Any tablet outside the acceptable limits is rejected. Forces are specific to a tablet press model, although the concept is applied for all. Tablets or filled capsules can be subjected to weight check as well. Normally, higher tolerance limits for weight checking are maintained, which are tighter than the values in the master document.

 Low API % w/w in the formulation is considered a high risk factor due to potential segregation after final blend and a high risk for content uniformity. Therefore, a product with low unit weight and low API content can be selected to further evaluate the minimum tableting batch size. This factor can also be used to determine variability within a batch for a particular product. Data of comparable campaigns can provide a reasonable indication of the anticipated batch-to-batch variability. The magnitude of the batch-to-batch variability can be dependent on several different factors; one factor in particular is the API content or product label claim. To gain an understanding of batch-to-batch variability, historical dosage uniformity and dissolution data from a large number of campaigns (e.g., more than 200 Stage 2 campaigns encompassing over 700 individual batches and approximately 100 distinct molecules) can be compiled. The batch-to-batch variability can be extracted from each campaign by separating the intra-batch variability from the overall total campaign variability. The data can be then segregated and analyzed to assess the relative influence of several factors (e.g., manufacturing process, strength, batch size). Product active content or strength has a high probability to be a factor that correlates to batch-to-batch variability. Typically, batch-to-batch variability for both content uniformity (CU) and dissolution significantly increases for low-strength products (<1 mg). Thus, one relevant factor for batch-to-batch variability is active content or strength (7).

Another factor that affects the minimum required dosing batch size is the manufacturing process. For example, the potential for segregation is minimal with hot-melt extrusion processes, in which the API is formed into agglomerates by melting of liquid binders. A direct mix manufacturing process has a higher potential for API segregation than a compacted process wherein the API is locked into granules. Therefore, a product with low API content and low unit weight from a direct-mix manufacturing process and high API content and high unit weight from a granulation manufacturing process may be considered as extreme cases for the assessment. 

Start-up waste from similar product/process.

 Start-up waste is generated due to initial adjustments to achieve the in-process quality attributes (i.e., tablet weight, hardness, thickness, friability, and disintegration) prior to starting the compression process. Process performance qualification samples are collected after start up, where all the in-process specifications are achieved at an established consistent tablet-press speed. In-process quality attributes are maintained by the force-control mechanism throughout the compression process. Because the tablets manufactured as start-up waste are disposed of, the start-up waste generated should be considered for the minimum batch quantity requirement.

	Based on these four factors, the product portfolio can be assessed and summarized as shown in 

			Table II. Summary of product information. CU is content uniformity, CpK is process capability, and Pa is acceptance probability*.			

	The assessment is based on an underlying assumption that the equipment qualification and calibration tolerances of key parameters were considered, and that a compliant quality management system is in place to detect any adverse trends or deviations. Additional factors can be added to the assessment. A minimum dosing batch size can be assigned based on the factors (tablet weight, API percentage, manufacturing process, start-up waste) as well as equipment capacity/capability (e.g., hopper feeder, powder bowl capacities) and regulatory market requirements, with the underlying assumption that the product has an established control strategy. Application of a minimum batch size based on the described strategy is of low risk for the product with a defined manufacturing process from Stage 1: process design, confirmed at Stage 2: process performance qualification, continually monitored as part of Stage 3: continued process verification, and with a control strategy established, including in-process controls. Jana Spes, vice-president of Technical Operations, Apotex, summarizes that variable batch sizes for semi-continuous processes such as tablet compression and encapsulation, without compromising product quality, allows for operational flexibility and efficiency. With regulatory acceptance of continuous manufacturing technologies and the associated minimal impact of batch sizes, it is time to reconsider the approach to batch-size determination for traditional semi-continuous manufacturing processes as well.

		S. Chatterjee, “FDA Perspective on Continuous Manufacturing,” IFPAC Annual Meeting (Baltimore, MD, January 2012).	

Guidance for Industry: Immediate Release Solid Dosage Forms Scale Up and Post Approval Changes

Draft guideline on manufacture of the finished dosage form

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


	Naheed Sayeed-Desta is manager, Process Validation, 

; Ajay Pazhayattil is associate director, Process Validation; and Srihari Chowdari is manager, Technical Operations, all at Apotex.

 Supplement
	September 2016
	Pages: s16–s19

:
	When referring to this article, please cite it as N. Sayeed-Desta, A. Pazhayattil, and S. Chowdari, "Determining Minimum Batch Size," 

Flexible batch sizes for semi-continuous unit operations, such as tableting and encapsulation, can improve efficiency while maintaining quality.