Mapping information flow across multiple service providers requires a paradigm shift in organizational thinking
Pressure and scrutiny from regulators, customers, and stakeholders continue to drive the pharmaceutical industry to search for alternate ways to produce quality medicines at reasonable cost. But business models for development and commercialization of pharmaceutical products have changed significantly. Over time, operations have moved from in-house clinical and technical research, development, and commercialization activities to approaches that utilize and build upon the strength of smaller but specialized organizations – contract service providers (CSPs).
CSPs are holders of many of the activities required for bringing new pharmaceutical products to the marketplace and keep them manufactured in the desired geographical region as part of an ever-evolving supply chain architecture. While the framework for best practice to generate the desired knowledge and materials during the product life cycle is, by and large, in place via FDA, EMA, and ICH guidance, the complexity of having to align and integrate the attenuating activities that saveguard quality of the therapeutic product is significant.
That is why, to manage supply and increasing demand complexities, product license seekers and owners now need to run their operations in a vastly different manner to remain in compliance with the modern regulations focused on quality and reliability.
Accountability Matters…
What hasn’t changed is the accountability of the license seeker or owner to keep guard at all times and to ensure patient safety through managing the objective evidence generated by the different parts of their operations. The knowledge generated and shared across different groups must create a solid foundation for successful commercial operations prior to market introduction and for post market approval.
Quality and reliability have to be built into product realization itself to keep pace with accelerated approval timelines and the escalating regulatory and compliance demands of new and advanced drug therapies.
…As Business Complexity Increases
Highly branched outsourcing and licensing activities can be generated on the product development from the time a drug candidate is discovered and biologically or genetically validated for its therapeutic potential; it will be evaluated for its drug-ability potential, proven to be toxicologically safe, and later safe in humans before being the subject of large investments to prove its clinical efficacy for the target disease and its commercial realization.
Activities on the clinical and CMC (Chemistry, Manufacturing, and Controls) path are often outsourced to multiple contract organizations for specific capability or capacity reasons.
Speed to market and costs associated with development of new therapies are often drivers to outsourcing and license agreements; the benefits that come from leveraging platforms that include highly specialized skills along with facilities designed to effectively execute selected operations are of high value to the overall development throughput.
Specialized organizations for clinical, regulatory, technical, and commercial development are being targeted for services by large pharmaceutical firms looking for novel business models and by startups or small size companies in search of capabilities to advance their assets.
The complexity associated with using multiple CSPs for knowledge and materials generation during development of one (bio)pharmaceutical product or a platform of similar products is multiplied for companies with portfolios composed of highly different modalities and drug candidates (i.e., recombinant proteins, peptides, Mabs, biosimilars, cell therapy/gene therapy, etc.) requiring very different types of expertise and services.
All operations need to manage increasing complexities to reap the benefits of bringing to market more effective therapies to compete with treatment of a targeted disease state. The “lighthouse” for reliable value creation is built upon the quality of knowledge generated and integrated across the pathway.
Four Frameworks for Phase-Adapted CMC and cGMP Pathways
The intersection between the quality systems used by sponsors and contract service providers can create “sticky” points as the product advances through its life cycle. The information generated under highly broad GxP requirements can create significant disagreements regarding the requirements applicable for the generating results specially for highly specialized CSP. Complexity can also create uncertainty in how information should be generated and aggregated along the way, especially for start up companies that have an early phase asset and are using partnership and contract organizations to develop it.
These four frameworks can shape increasing traffic flow at intersection points embedded in both internal and outsourced business models.
- Frame it from the top: use a quality manual to project a value driven quality system
- Deploy a phase-adapted quality system
- Use science to define quality and achieve compliance
- Proactive governance: prepare early for success at transition points
Figure 1. Increasing Complexity with Outsourcing - Knowledge and Materials Generators across the CMC development pathway.Frame it from the Top with a Quality Manual
Figure 2. Using QMS to drive effectiveness in outsourced business models.Enforced by FDA 21 CFR 820, the quality manual (QM) is a document with high applicability and utility across industry sectors that goes beyond medical devices and related services. It documents a company’s Quality Management System (QMS) to demonstrate its ability to consistently provide product that meets customer and regulatory requirements. A quality manual established first from the framework of where business is done (sites, location, CSP, partners, etc.) can subsequently establish and tailor the applicable quality systems and adapt cGMP to best define how business is done at every location, for the work stream required in every phase of the development cycle.
The quality manual can be used as the top-level foundational document of a quality management system. It has been described as something similar to a country’s constitution or a party manifesto; in this case it pertains to an enterprise. As a document the quality manual should refer to the policies, systems, and procedures intended for planning and administration of activities and interaction between the processes of the QMS.
A well designed quality manual can define the architecture required for effective execution while managing the risks at the intersections between the parts of the internal/outsourced business partners focusing.
The quality manual of a license owner should illustrate the end-to-end business with the rules governing the different groups linked on the value creation pathways. Visibility and clarity of the business model at the quality manual level may reduce the complexity of the overall QMS architecture. It can also increase flexibility, and improve communication across the enterprise and externally.
A sponsor’s quality manual will reflect where and how the company does business. It can specify what activities may be carried out internally and externally, and by when the information will enter a targeted gate in the product life cycle (pre-clinical, Phase 1-3, post approval, etc.).
QM: Sum ((#Sites , #CRO, #CDMO, #CMO /Operation)/GxP)
The task of creating a quality manual that incorporates phase-appropriate CMC and cGMP activities becomes a company’s commitment to satisfy those requirements with the appropriate level of details. It will become the starting point to develop and document policies that are simple to understand, and include user-centric procedures (such as SOPs, work instructions, etc.).
For service providers, a well-written and communicated quality manual incorporating phase adapted activities for different categories of sponsors will become a powerful business advantage, promoting a quality-conscious mindset and cost effectiveness business.
A service provider specialized in either pre-clinical, clinical, or commercial activities may specify in their quality manual how their Quality Systems are applied in what facilities, laboratories, processes, etc.
QM: Sum (#Site/Service/GxP)
A tailored and intentionally crafted quality manual can set up the framework for creation of the desired quality culture. The value of the QMS can be assessed using process mapping tools across the partnerships charted in the quality manual, and across processes encompassed by the QMS. Periodic process mapping will drive continual alignment and improvement between different parts of the business, combining the value of quality driven knowledge acquisition with operation excellence
Quality Value Stream Mapping (QVSM) can complement the classical process stream mapping with specific quality-related elements to visualize, analyze, and improve quality issues within a process chain. These elements include product generating processes, flow of materials, quality defects, quality inspections, and quality control loops as part of QVSM. The status of the quality control along the process chain is evaluated in terms of key indicators with regard to quality and quality-related costs.
Deploy a Phase-Adapted Quality System
A well-adapted QMS that best represents the enterprise operating structure can infuse clarity, simplification, and effectiveness in execution. The processes and procedures to produce objective evidence (data, documents, knowledge, products) required for IP protection, pharmaceutical product development, and commercialization will follow the local reflection of the QMS.
Phase-appropriate Good Manufacturing Practices (GMPs), cross-linked with Chemistry, Manufacturing, and Controls (CMC) development deliverables, and mapped across multiple service providers require a paradigm shift in organizational thinking.
The goal is to implement tailored and value enhancing quality systems (QMS, PQS) while simultaneously establishing a non-disruptive way to transition from one development phase to another, with regard to each of the CMC elements (Drug Substance, Drug Product, Analytical testing, etc.).
A phase appropriate cGMP operating model is highly relevant for companies that have a high level of externalization of their R&D and early clinical development activities. It will simplify the intersection of different QMS systems; it will allow to focus on quality rather than compliance and will modulate expectations.
Lining up the quality system and cGMPs with activities taking place in different phases of development is a paradigm that is recognized and enabled by regulators. A great illustration for a gradual implementation of cGMPs and Quality Systems from R&D through Phase III development of a Biological API was published by PDA in Technical Report 56 in 2016.
Such explicit illustration made available to all groups involved in execution will be the basis for the next level of alignment. 1) Alignment on the “Compliance Tolerance” between different organizations liked to receive and advance development within an early development phase 2)Alignment on processes to expedite decision-making related to relevant criteria, data acceptance, managing atypical results investigation based on relevance and risk associate with utilization of results.
Auditing the Quality Systems of a service provider or supplier is required but it is not sufficient if the goal is to operate under a value enhancing and tailored QMS. Onsite evaluations walking onto a manufacturing floor or laboratory and observing the quality culture and the QMS in action will provide the next level platform on which alignments on compliance and decision making policies should be formalized.
The most important element of the QMS remains the people and their commitment to quality, grounded in foundational knowledge.
Use Science to Define Quality and Achieve Compliance in Early Development Phase
Development scientists are engaged in the mission to establish the information that will best provide the understanding of the molecule, the product, and the processes behind a Target Product Profile and its robust quality. In most organizations quality scientists are part of the CMC teams and have the mission to guard compliance with regulations relevant to the applicability of the data.
In a phase-adapted paradigm, especially in early phase when products are just passing over proof of concepts, when the knowledge base for the molecule, product, or technology is being built, the acceptance criteria for results acquired to establish the SISPQ (Safety, Integrity, Strength, Purity and Quality) must be governed by “fit for purpose” with focus on quality rather than compliance. The scientific understanding and ability of the information to mitigate risk to the patient and advance the target product profile is the best definition of quality. Risk and science based criteria should be the basis of early phase control strategies, to establish ways to manage investigations when dealing with an unexpected result. Science based understanding will set up the path toward identification of the critical quality attributes, critical process parameters and a reliable product design space.
Proactive Governance: Prepare Early for Success at Transition Points
Quality and technical governance processes when captured in the quality manual sets a clear path and expectations for the knowledge flow and risk assessments at transition points between business partners, phases of development, or product platforms. Phase gate reviews are processes rooted in six sigma DMAIC and will install discipline by setting acceptability of information to move to the next phase with the right technical and business considerations.
High value can be created across the enterprise when a good understanding of end-to-end processes is combined with nimble phase-appropriate execution. A non-disruptive transition from one development phase to another is the signature of a highly integrated organization, and a well-managed outsourced business. However, the flow coming up from different parts of the value stream is not always at the right level, just as, over the course of a river, the water is not always at the right level to allow navigation. Water locks are simple and ancient marvels of engineering that follow the same principles today. Metaphorically speaking, technical transfers especially towards late commercialization phase, are just like water locks, making transition to the next level possible.
The knowledge resulting from a progressive integration of information acquired by different analytical, formulation, process development, engineering, quality, regulatory, clinical, and toxicological groups will position the product for transition to the next development phase. In the absence of proactive and continual assessment of readiness for the next phase, significant gaps can be identified creating disruptions and delays.
In the case of a complex network of service providers, actions are often taken to create smaller structures with the responsibility to manage immediate or urgent activities linked to readiness for technology transfers. The need for such ad-hoc groups can be moderated by the governance structure defined in the QMS and business agreements.
Integrated technical reviews should be set up periodically and in advance of pivotal transition points. Risk assessments and risk mitigation plans should be in place for course correction and set up the next level development investment for success.
The QMS may create the framework for the traffic flow of information and for the governance process associated with the flow if knowledge and materials from different parts of the organization come into play.
Summary
There are benefits and also increased complexities caused by business outsourcing models in an industry characterized by a high diversity of therapeutic products and medical technologies.
Industry continues to search for ways to simplify and streamline development activities while having to incorporate industry best-practice concepts such as quality by design (Qbd) and expectations set up by regulators worldwide. Phase-adapted development requires deployment of frameworks that bring clarity and simplification from the top of a QMS that drives value in execution for sponsors and service providers alike.
References
- PDA Technical Report 56:Application of Phase-Appropriate Quality Systems and cGMPs to the Development of Therapeutic Protein Drug Substance (API or Biological Active Substance)
- Guidance for Industry CGMP for Phase 1 Investigational Drugs
- EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 13 Investigational Medicinal Products
- Guidance for Industry INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information
- Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
- Title 21-FDA Department of Health and Human Services-Subchapter H-Medical Devices: Part 820 Quality System Regulations
- Quality Value Stream Mapping Benjamin Haefnera, Alexandra Kraemera, Torsten Staussa, Gisela Lanzaa; Procedia CIRP 17 ( 2014 ) 254 – 259 Proceedings of the 47th CIRP Conference on Manufacturing Systems
Dr. Mihaela Simianu, Director of Regulatory Compliance at Pharmatech Associates brings leadership, knowledge and experience in the Regulated Life Sciences industry from a career spanning over two decades. She is a long time member of the Parenteral Drug Association (PDA) and serves on the task force for PAC iAM (Post Approval Changes Innovation for Access to Medicines). She has been a speaker and member of planning committees for conferences on injectable drugs and biologics topics. Before joining Pharmatech, Simianu served as Amgen’s Executive Director of Parenteral Product and Process Development in Thousand Oaks, Calif. She previously worked at Eli Lilly’s Research Laboratories (Indianapolis) and led global Manufacturing Science and Technology groups in various senior roles. Simianu holds a Ph.D. from Marquette University and completed post-graduate work as a research fellow at the University of Nebraska-Lincoln.