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An effective quality control unit is independent from manufacturing and ensures current standards are followed.
The safety and efficacy of pharmaceutical products is of utmost importance. Regulations in the United States require that pharmaceutical companies establish a quality control unit to perform quality functions to ensure their products meet specifications and are safe for use. This unit also has the task of assuring regulators that good manufacturing practices (GMPs) are being followed. Regulators in Europe and other parts of the world have similar but varied requirements.
The consequences of failing to ensure the quality of drug products range from the most egregious-adverse effects on patients-to potential regulatory actions, such as consent decrees, import bans, and seizure of product. Regulatory responses can include reports such as FDA Form 483 observations, inspection findings from the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, or requests for urgent actions such as FDA warning letters. In addition to regulatory actions, an ineffective quality system may also affect a pharmaceutical company’s success. “Ultimately the consequences are reduced profitability, as scrap, rework, and downtime are increased,” says Karen Ginsbury, CEO of PCI Pharmaceutical Consulting Israel Ltd.
Warning letters issued by FDA to various pharmaceutical companies located in the US and around the world in 2019, however, seem to have a common theme: a lack of a properly functioning quality control (QC) unit (1–4). The agency has cited companies for everything from failure to establish an adequate QC unit to QC units not performing their duties properly.
“Many FDA 483 observations have been issued for quality units failing to fulfill all their responsibilities. If a firm releases product (or other material) in the absence of a quality unit, this is even more egregious,” says Mary Oates, vice-president compliance services, at Lachman Consultant Services, Inc. “There may also be consequences for patients. If there is no quality unit, in all probability there will be significant gaps in the pharmaceutical quality system, potentially presenting risk to patients if processes and controls are not in place to ensure product quality.”
Pharmaceutical companies are responsible for ensuring the standards of all drug components, including excipients, APIs, and packaging materials, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow at Regulatory Compliance Associates, and it is the QC unit’s responsibility to investigate why any of these components fails to meet those standards. “The quality control unit plays a huge part in making sure that products meet the proper applicable standards before they are released,” says Schniepp. “It’s interesting to note that the quality control unit is the only functional unit required by law. This is not to imply that the quality unit works in a vacuum, but rather that it facilitates the investigation into any failures. [The QC unit] has the sole responsibility of releasing product. No other department in an organization has this authority, and it cannot be delegated. Bottom line, we rely on the quality unit to make sure that product released to the market is safe and effective.”
With quality being so imperative, how is it that pharmaceutical companies are improperly maintaining such a vital part of their operations? One could argue that a failure to create a quality culture in the organization from the top to bottom may be a cause for this failure. The following discusses why companies may be faltering in this area and what a company can do to maintain a more effective quality control unit.
One of the challenges in ensuring quality may be the varied regulations and requirements pharmaceutical companies must follow. When it comes to the QC unit, there seems to be some confusion and debate about what exactly a QC unit is and what duties it performs. This confusion can be somewhat blamed on different names for the quality department itself and the language in the US and EU regulations.
According to Ginsbury, the message in the GMP regulations is unclear and possibly misleading. “Based on the definitions in the GMPs, we can conclude that in the United States and the European Union, the QC unit apparently has a rather narrow role, limited to sampling, testing, and making judgements as to product quality (or lack thereof, i.e., release/reject). This is not necessarily, nor ever was, the intent of the regulator,” insists Ginsbury. The GMP regulations are more product than process focused, says Ginsbury, “which can result in executives mistakenly believing that product meeting all release specifications may be released even when there are some serious GMP deviations related to the batch or other batches of product, or equipment or facility.
“Under QC unit roles, there is not much to be found at all about establishing, maintaining, and continuously improving the quality system, measuring (quality metrics), and reporting to management as to how well the system is doing,” Ginsbury continues. “The QC unit is perceived as a sort of judge, who with unusual wisdom can ‘decide’ if faulty/flawed product produced with a deviation or non-conformity is ‘impacted’ or not impacted by the non-conformity. The concept of zero defects and prevention of defects, which is the basis for any true quality system, and the Plan-Do-Check-Act process-based cycle are absent [in the written GMP regulations].”
Russell Madsen, president of The Williamsburg Group, LLC, argues that, in the US, the QC unit has “sweeping responsibilities specified in 21 Code of Federal Regulations (CFR) §211.22, including ‘the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product’” (5).
So, what is a QC unit? US 21 CFR 210.3(15) defines the quality control unit as “any person or organizational element designated by the firm to be responsible for the duties relating to quality control” (6).
According to Oates, the QC unit includes both quality assurance (QA) and quality control functions and should be involved in the approval of the drug product, testing results, production records, procedures, and all materials that might affect the final drug product whether that product is produced in house or “manufactured, processed, packed, or held under contract by another company,” says Oates.
Both Schniepp and Ginsbury state it is important to understand the difference between QA and QC. Ginsbury further states that neither of these on their own are what the regulator intended regarding the QC unit. “The quality unit should be […] preventing defects and non-conformities from happening by planning (including proactive risk assessment/management during design of processes, checking [validation]), monitoring, and continuous improvement,” says Ginsbury. “This needs to be real time and not as current Product Quality Reviews are performed-annually with a lag of up to 18 months from when the data [were] collected.”
The QC unit should be independent from manufacturing and should serve as oversight for the overall quality system and set the quality culture within the company. “The [QC] unit can be seen to have two tasks: quality testing and the decision to pass or fail on the basis of the results. These two functions are usually separated into a quality control laboratory (testing) and quality assurance (release and documents administration). There is a good reason for this because it takes the release decision away from the testing group and keeps it independent,” says Chris Moreton, partner at FinnBrit Consulting. Oates agrees, “The quality unit itself manufactures nothing. It is responsible for oversight.”
This independence contributes to overall product quality, says Oates, especially when it comes to quality decisions and the commitment to delivering quality products. “All firms in the pharmaceutical industry, no matter the size, must have robust processes and systems to enable right-first-time manufacturing (inclusive of all GMP activities along the supply chain) and, perhaps most critically, a culture that puts the interests of patients first. Only then will product quality be assured,” says Oates.
In Europe, the batch release/reject decision falls to the role of a Qualified Person (QP) as defined in the European guidelines (7, 8). Europe Directive 2001/83/EC (9) states, “Member States shall take all appropriate measures to ensure that the qualified person referred to in Article 48, without prejudice to his relationship with the holder of the manufacturing authorization, is responsible, in the context of the procedures referred to in Article 52, for securing: (a) in the case of medicinal products manufactured within the Member States concerned, that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization. ...”
An understanding of the role of the QC unit is the first step in creating and maintaining the QC unit. A company’s standard operating procedures (SOPs) must clearly define the role of the QC unit, says Oates. Processes that are clear and easy to follow in repetition should be implemented, agrees Bo Henry, director of quality control at Catalent. Documentation should be standardized, and staff should be trained to ensure the integrity of data. “Finally, build a culture focused on the patient. With an effective training program and a culture of quality, the entire organization will be able to approach decision making effectively,” says Henry.
The makeup of the unit is the next important step. The QC unit should be comprised of personnel with knowledge of the products and processes they oversee, says Madsen, and should be familiar with the GMP regulations. Oates agrees, “They must understand the processes and systems for which they have oversight. For example, an employee in QA responsible for oversight of aseptic media fills must fully understand the critical aspects of aseptic manufacturing, grasping the ‘why’ as well as the ‘what.’ Ideally, a quality control unit would include some employees who have prior experience in manufacturing. This deeper understanding of the production processes and systems enhances their ability to provide appropriate oversight,” says Oates. According to Ginsbury, in Europe, these requirements are stated in the EU GMP guidelines (10).
According to Mark TePaske, senior director, global regulatory affairs, quality and compliance at Cambrex, the nature of pharmaceutical products requires more stringent controls than other industries. QC personnel operate complex analytical instruments and must follow approved written procedures, says TePaske. “QC needs metrology resources (often contractors) to qualify and maintain instruments; analysts to set-up and operate instruments and perform tests methods; persons to qualify/validate test methods; technically competent persons to draft procedures; personnel to perform peer review of data and supervisors (as required by the FDA out of specification guidance document ), support investigations and troubleshoot; and persons to approve and report results. All personnel need to be suitably trained by qualified trainers with training documented. This list assumes that QC relies on [the quality assurance department] for document control, issuance, and retention,” says TePaske.
A QC unit should consist of personnel from quality assurance, quality control, validation, and sterility assurance departments, according to Henry. It may also include personnel from document management and quality engineering. All personnel must understand how their role ultimately affects patients, says Henry. “It is also critical to align with all applicable regulations and guidance for the product. Start by creating a quality manual, then build foundational standard operating procedures. Performing an initial process map of the quality and operational processes prior to generating quality management system policies and procedures is a very useful exercise,” says Henry.
The key aspects of an effective QC unit include well-written SOPs, well-informed personnel, and a clear understanding of roles and responsibilities of everyone involved. The development of a quality culture throughout the organization is also important. Ginsbury stresses that developing this quality culture is only possible if executive management is brought on board.
To ensure continued quality and uninterrupted supply of pharmaceutical products that are distributed to patients, the QC unit must stay apprised with changing GMPs, says Oates. Procedures that at one point were compliant with the regulations may no longer be. “This is often seen in the areas of validation and aseptic manufacturing. Regulatory expectations are increasing, and some firms are not remaining current,” says Oates.
Written procedures must be developed and followed according to the regulations. These procedures should be thorough and complete, says Oates. “For example, validation for a manufacturing process may not have been completed or the responsibilities of the quality unit may not be defined in a procedure.” Procedures that lack sufficient detail can lead to quality problems, says TePaske. “The most common problems here are that some procedures lack enough detail to ensure control, other procedures omit required information (e.g., the FDA out-of-specification guidance document includes an extensive list of considerations), and some procedures contain too many or contradictory details and are impossible to accurately follow.”
Each individual’s role within the QC unit and the organization must also be clearly defined, says Henry. “The plan should outline which individuals need to be informed of a deviation, and who can make the decision on next steps if the next steps are not captured already in the procedure. As an organization grows, it can become difficult to maintain clarity on written procedures as more people are trained and asked to execute the procedure with a reproducible result. It is extremely important to revisit the procedure at an established frequency to revise it as needed for clarity.”
Failure to develop and follow such procedures may lead to regulatory actions. “When a firm receives a finding regarding the quality unit, it must look more holistically at its controls than perhaps is evident from the observation itself,” says Oates.
There is also the problem of a “misalignment” of practices and written procedures, according to Oates. “Operators may execute a manufacturing process in one way while the SOP indicates it should be done differently. Additionally, it is possible that the validation document may not be aligned with either the actual or written practice,” says Oates.
Ensuring that deviations are properly investigated is also imperative for the QC unit. Oates stresses that it is the QC unit’s responsibility to define what constitutes a deviation and that this definition must be clearly communicated to the rest of the organization. “Training with examples must be provided so that the understanding of what is a deviation is fully calibrated across the organization,” says Oates.
The QC unit must have a system of “escalating” the investigation and resolution of deviations. Root cause must be identified and corrective actions and preventive actions (CAPAs) should be established. Henry states that investigations should remove human performance from the equation. “Most importantly, the product strength, identity, safety, purity, and quality should be considered when determining the impact of the deviation and ultimately the overall integrity of the batch by the quality control unit.”
“Firms can fall into a trap of being more focused on product release than on completing a holistic investigation, and the quality unit has the obligation to ensure the investigation is complete and appropriately supports any decisions being taken,” says Oates. Any trends found across multiple investigations should also have CAPAs implemented, and the QC unit should look for common themes. “Continuous improvement must be an objective of the quality unit and the firm as a whole,” says Oates. “Attention must also be given as to whether regulatory notification is required in a prescribed timeframe.”
“Top management and the QC unit must work in harmony to ensure there are adequate resources to investigate and correct situations that result in deviations. The importance of finding and correcting root causes cannot be overemphasized, so that deviations do not recur and overwhelm the organization,” stresses Madsen.
Establishing a quality culture throughout the organization is an important way to ensure that these steps are being taken. “It all comes down to training and motivation. Everybody, from the most junior to the most senior members of the organization, should be thinking ‘Quality’. This [quality culture] is obviously important in manufacturing and quality groups, but it is also important in finance, marketing, sales, etc,” says Moreton. “For example, there are always pressures to contain costs, but this should not be to the extent that people tend to gloss over things because there is not time or resources to deal with it properly. There are pressures to get the medicinal products into the supply chain as quickly and efficiently as possible, but this should not compromise patient safety,” says Moreton.
An effective QC unit must be independent of the manufacturing unit, says Oates, and the QC unit’s final decision on the release of product must be respected. “It is never appropriate to pressure the quality unit to release product to meet business needs if the product is not acceptable for release,” says Oates. “The quality unit must have a single, final decision-maker who is ultimately responsible for quality decisions.”
Pharma company executives should be aware that the quality of their products is a responsibility of many components of the organization and not the sole responsibility of the QC unit. “Perhaps the biggest mistake is for the firm to assume that the quality unit is responsible for quality. Manufacturing is responsible for product quality. The quality unit provides the framework in which GMP activities occur and subsequent, ongoing oversight and support for continuous improvement,” says Oates.
Ultimately, a successful quality control system requires a dedication to quality and investigating problems. “Small issues have a way of snowballing. Additionally, quality units cannot ensure product quality. Product quality can only be ensured when all company organizational units work in harmony, with product quality and patient safety as their primary goals,” says Madsen.
1. FDA, Warning Letter to NingBo Huize Commodity Co., Ltd., Aug. 2, 2019.
2. FDA, Warning Letter to Spectrum Laboratory Products, June 4, 2019.
3. FDA, Warning Letter to Kingston Pharma LLC, May 14, 2019.
4. FDA, Warning Letter to Pharmasol Corporation, March 14, 2019.
5. FDA, Responsibilities of Quality Control Unit, 21 CFR §211.22.
6. FDA, Current Good Manufacturing Practice In Manufacturing, Processing, Packing, Or Holding Of Drugs; General, Definitions, 21 CFR §210.3 (15).
7. EC, EudraLex–Volume 4–Good Manufacturing Practice (GMP) Guidelines.
8. EMA, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use, Nov. 28, 2004.
9. Directive 2001/83/EC of The European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal products for Human Use, Nov. 28, 2011.
10. EC, EudraLex-Volume 4–Good Manufac–turing Practice (GMP) Guidelines, Annex 16.
11. FDA, Guidance for Industry, Investigating Out-of-Specification Test Results for Pharmaceutical Production (October 2006).
Vol. 43, No. 11
When referrring to this article, please cite it as S. Haigney, "The Right Pieces for a Quality Program," Pharmaceutical Technology 43 (11) 2019.