The market expectations for reliable products and robust supply chain influence industries regulated by FDA. Shorter development cycles along with market competition, force companies to evolve faster. An alternative to stay abreast is to outsource services to skilled and focused vendors. No matter who is contracted, requirements do not change with market trends as do the regulations from agencies such as FDA and alike abroad.
However, the addition of a contracted service to your operations brings new challenges that sometimes are over sighted. This article intends to bring an overview of those other liability issues that should be taken into account when engaging in outsourcing.
FDA Overview
The congress has the power to regulate the stream of commerce by virtue of the US Constitution that allows the regulation of trade between the states. Such congressional authority is channeled through the creation of federal agencies to regulate the myriad of effects from commercial trading; some examples are EPA, USDA and FDA. By virtue of Title 21 of the Code of Federal Regulations, the Food and Drug Administration is an administrative agency within the Department of Health and Human Services. FDA is responsible for regulating and supervising the safety of foods, dietary supplements, drugs, vaccines, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics. Their jurisdiction is across all 50 states and territories and does not include jurisdictional authority out of USA.
The Food and Drug Administration cannot regulate by enacting laws. Since they are an administrative agency they lack such authority and instead issue regulations. These are legal restrictions that attempt to produce outcomes which might not otherwise occur. Federal and State Courts have extreme deference to agency’s expertise and at trial regulations are treated as statutory laws. For some instances the FDA issues what are called ‘guidelines,’ which aim to streamline particular processes and are not considered mandatory. However, they are very persuasive when inspection issues and warning letters are written against a manufacturer.
When we add a contractor to the operation, additional obligations attach by virtue of contract law, agency and torts. By contracting, the client (e.g., NDA holder) becomes the principal in an agency relationship where potential negligence actions, as well as product liability issues, could lead to a joint or individual responsibility by either the client or the contractor (vendor). These elements are in addition to the FDA regulations that are applicable to the contractor by servicing a client where GCP, GLP or GMP regulations apply.
Both the client and contractor should be familiarized with the following:
- Negligence – conduct that is culpable because it falls short of what a reasonable person would do to protect another individual from foreseeable risks of harm. A CMO and the Client can be found joint tortfeasors depending on the facts.
- Product liability - impose responsibility on manufacturers, distributors, suppliers, retailers, and others who make products available to the public for product-related injuries. (e.g., design, manufacturing and labeling). Product design liability is not transferable to the CMO if they have not been contracted nor engaged in design activities.
- A contract is law between contracting parties and enforceable in a court of law and CMO may be responsible on a civil and/or criminal level based on what is contracted.
Navigating through the maze of liability from governmental and civil forces may seem to be unbearable if we try to engage in the FDA regulated business. However, there are common root causes and alternatives that lead to effective regulation compliance, as well as to significantly reduce civil liability. By implementing quality at the design stage, following strict regulations within your industry, having an effective quality and documentation system as well as an effective risk management program; the risks associated with civil or criminal liability for NDA holders and contractors are significantly reduced.
Quality-by-Design (QBD) Initiatives
The product quality is not a result of effective inspection, rather an effort of building quality-by-design. Quality should be built into the product with a thorough understanding of the product and the processes that manufacture it, as well as the understanding of the risks involved and how best to mitigate those risks.
Quality-by-Design is a concept that resumes the learned lessons of product design and development to carry out reliable and safe products as they are developed. It is accomplished by the full understanding of how product attributes and process relate to product performance based on scientific, risk-based, holistic and proactive approaches to product development, product specifications and the effective deployment of process controls at every stage where a critical product characteristic is made. QBD is not a one stop ending process, rather it engages in a never-ending loop of process improvement where risk to quality-by-design is mitigated.
In that regard, FDA has implemented a pilot program to allow manufacturers in the pharmaceutical industry to submit information for a new drug application demonstrating use of QBD principles, product knowledge, and process understanding. Although this has not been an official and across the board exercise from FDA where all new applicants have to go through, there are many benefits that QBD brings to the table such as:
- Enhances scientific foundation for review
- Provides for better coordination across review, compliance and inspection
- Improves information in regulatory submissions
- Provides for better consistency
- Improves quality of review (establishing a QMS for CMC)
- Provides for more flexibility in decision making
- Ensures decisions made on science and not on empirical information
- Involves various disciplines in decision making
- Uses resources to address higher risks
Quality Systems
The journey to quality and regulatory risk mitigation do not end with the design phase of the product. There are other equation variables once the product becomes a manufacturing target. Design can be at its best, but if the manufacturing process is deficient the product is at risk of causing quality or safety incidents that could lead to regulatory or civil liability. On the other hand, product design, coupled with a robust manufacturing process compliant to regulations and industry practices, leads the way to a reliable supply chain and customer satisfaction.
The Good Manufacturing Practices as pronounced by the FDA in 21 CFR, although regulations, are the minimal requirements expected in a product and its manufacture. Through guidance the FDA, as well as The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), have made available recommended approaches that give more direction to good manufacturing practices within the pharmaceutical industry.
One of ICH Q10’s advantages is the merging of requirements from different market zones such as the European Community, Japan and USA. This guideline applies to the systems supporting the development and manufacture of pharmaceutical drug substances. The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages; Pharmaceutical Development, Technology Transfer, Commercial Manufacturing and Product Discontinuation.
Successful implementation of the Q10 model should result in achievement of three main objectives which complement or enhance FDA GMP requirements, as well as international regulatory expectations within product realization, establishing and maintaining a state of control and facilitate continual improvement.
Quality Risk Management
A plan to improve quality and reduce regulatory and civil liability is not completed without the management of risks. ICH Q9 provides guidance on how to conduct risk management within pharmaceutical business with great details. This guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality.
Based on two primary principles, the evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.
Decision makers should take responsibility for coordinating quality risk management across various functions and departments of their organization; and assure that a quality risk management process is defined, deployed and reviewed and that adequate resources are available.
To initiate a Quality Risk Management Process we must define the problem and/or risk question, including pertinent assumptions identifying the potential for risk. This encompasses assembly of background information and data on the potential hazard, harm or human health impact relevant to the risk assessment. Project leader and necessary resources have to be determined along with timelines, deliverables and appropriate level of decision making for the risk management process.
At its performance stage the risk assessment activity must answer questions such as: What might go wrong?; What is the probability it will go wrong?; What are the consequences?
Along with these responses there is a decision-making point to reduce, or in some instances, to accept risks. If risk is determined to be accepted, it should bear a response plan with it where its acceptable level is assessed, mitigation plans are drafted with a careful evaluation of balances between benefits and risks, as well as the determination whether new risks are introduced as a result of the identified risks being controlled. Periodic reviews and communication plans are expected after the first risk management exercise.
Becoming Compliant as Continuous Improvement Tool
Noncompliance to regulations and quality brings catastrophic consequences to the business and brand name. In the government regulatory arena the issuance of warning letters and consent decrees directly impact the business’ ongoing concern by staining the company name, prohibiting marketing products within USA or other regulated markets as well as debarment, fines and in the most critical cases, criminal prosecution. In the civil arena, the risk of civil suits based on product liability, contract breach and agency are real concerns in a contractor-client relationship where not just the client becomes liable for patient safety, as it could also impact contractors’ business depending on its involvement on the issue brought to court. In all these cases, monetary loss is the common denominator.
On the other hand, implementing quality-by-design coupled, with a good strategy for quality systems compliance and risk management, would enable risk reduction and liability prevention in all aspects of the business, the regulatory and civil. A successful implementation would merge these elements to make a positive impact to the supply chain and business growth by reducing process waste, product complaints, product liability and potential issues with regulatory agencies.
Key aspects to promote are the use of design review exercises even for marketed products, conscientious quality planning and management review of key quality drivers, as well as a robust documentation control system that would help keep in evidence the activities performed to manufacture a product and every inspection made before its release. Processes must be validated based on their worst-case scenario and associates trained to perform all tasks assigned. The closer we stay to a robust quality system, the less likely we are to encounter compliance risk.
Robust x (Product Design + Process Design + Quality System) = Compliance Assurance
References
- Implementing Quality by Design, by Helen Winkle, FDA http://www.fda.gov/Cder/OPS/ImplementingQualitybyDesign.pdf
- Pharmaceutical Quality by Design: Improving Emphasis on Manufacturing Science in the 21 st Century, by Ajaz Hussain, PhD (formerly of FDA) http://www.fda.gov/cder/OPS/PharmQual.pdf
- Engineering a Proactive Decision System for Pharmaceutical Quality, by Ajaz Hussain, PhD (formerly of FDA) http://www.fda.gov/cder/OPS/hussain_1_2005.pdf
- Implementation of QbD Principles in CMC Review, by Chi-Wan Chen, PhD, Deputy Director, Office of New Drug Chemistry http://www.slideshare.net/bergerb2/quality-by-design
- A FDA Perspective on Quality by Design http://pharmtech.findpharma.com/pharmtech/article/A-FDA-Perspective-on-Quality-by-Design/ArticleStandard/article/detail/469915
- Q9 - http://www.ich.org/LOB/media/MEDIA1957.pdf
- Q9 Final Business Plan - http://www.ich.org/LOB/media/MEDIA3611.pdf
- Q9 Final Concept Paper - http://www.ich.org/LOB/media/MEDIA3562.pdf
- Q10 Pharmaceutical Quality System - http://www.ich.org/LOB/media/MEDIA3917.pdf
- Q10 Business Plan - http://www.ich.org/LOB/media/MEDIA3356.pdf
- Q10 Concept Paper - http://www.ich.org/LOB/media/MEDIA3097.pdf
- Interaction Between the House of Quality (within Design for Six Sigma) and the FMEA (within Design for Reliability) http://www.weibull.com/hotwire/issue93/hottopics93.htm
- Contract Manufacturing, Robert Coleman – Retired USFDA investigator
- How to Eliminate Cost of Quality by Design http://www.halfcostproducts.com/design_for_quality.htm
Robert Guzman is the Managing Director for Sigma Compliance LLC, a consulting company focused on FDA compliance, training, GCP/GLP/GMP audits, process transfers and validations. He has 17 years experience in ISO and FDA regulated Pharmaceutical / Medical Device industries in corporate compliance, six sigma, quality systems/engineering, supplier management, validations, and process engineering within the domestic and international markets (Asia, Australia, Europe, South America and North America). He is a registered professional engineer in the state of North Carolina with a Law Doctorate from Pontifical Catholic University of Puerto Rico, MBA from University of Massachusetts and a Master in Chemical and Life Sciences from University of Maryland. Mr. Guzman can be contacted to [email protected]
This article was printed in the March/April 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 2. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.