Starting a drug development company on a shoestring budget presents significant hurdles. Particular challenges may present themselves for small startup companies manufacturing investigational new drugs (INDs) used in Phase 1 clinical trials.
Often these are small startup virtual companies – young, lean, and operating with limited funds and resources. How should these companies proceed to ensure the safety and quality of products without the full burden of commercial cGMPs?
A critical guideline to consider is the FDA’s Guidance for Industry on Current Good Manufacturing Practice (cGMP) for Phase 1 Investigational Drugs. This document emphasizes flexibility in applying cGMP activities that are more appropriate for Phase 1 clinical trials. Adopting phase-appropriate cGMP by tailoring the level of GMP rigor offers significant benefits by allowing smaller virtual companies to focus their resources on the critical aspects most relevant to early-stage development: ensuring patient safety and product quality.
To help virtual companies streamline their operations and ensure compliance, we recommend the following 10 foundational Chemistry, Manufacturing, and Control (CMC) SOPs, tailored for the early clinical stage of drug development.
1. Vendor Qualification, Oversight, and Audit
Setting up and maintaining in-house GMP facilities is extremely expensive and complex, making it impractical for most early-stage companies. It is very common for virtual startups to outsource much of the product lifecycle to Contract Development and Manufacturing Organizations (CDMOs/CMOs), making vendor qualification essential. A robust SOP should define the vendor management program to minimize the risks associated with the delegation of responsibilities to contracted service providers. This SOP should cover the lifecycle phases of vendor management including vendor identification and assessment, selection/approval, and monitoring/oversight.
Highlights:
- Criteria for vendor selection – Set standards for initial evaluation and continued qualification.
- Audit frequency based on risk level – Periodic reviews should be proportionate to the criticality of the vendor’s role.
- Ongoing performance evaluation – Establish a continuous review process to assess vendor performance and compliance.
- Vendor issue resolution – Define a process for managing and escalating non-conformances.
- Define requirements for vendor agreements – Define the need for Quality Agreements, Master Services Agreement or other similar documentation based on the criticality of the vendors.
2. GMP Quality Agreements
Even when companies outsource production, packaging, labeling, testing, and warehousing to external service providers, the company retains the ultimate responsibility for the quality and integrity of the GxP activity. Establishing Quality Agreements with high-criticality vendors ensures compliance with cGMP standards. A Quality Agreement should include clear terms that align with both parties’ expectations and regulatory obligations.
Highlights:
- Define terms – Include effective date and termination clause.
- Define activities and responsibilities – Delineate the responsibilities of each party with regard to Quality and Change Control.
- Specify vendor audit and evaluation provisions – Include the frequency of routine periodic audits, unlimited for-cause audits, and assistance with product-related regulatory inspections.
- Handling deviations and CAPAs – Set up a process for managing non-conformances and ensuring corrective actions are implemented.
- Communication channels – Define efficient communication protocols for daily operations and incident escalation.
3. Review and Approval of Vendor Documents and Record
Regulators expect companies to have effective control over their supply chain. Reviewing vendor documents is a key part of demonstrating due diligence. This SOP should define the systematic process for reviewing and approving vendor documents pertaining to GxP activities including but not limited to technical reports/protocols; analytical method transfer, qualification, or validation reports/protocols; deviation investigations, CAPAs, or change controls; specifications for starting materials, drug substance, or drug product; and master/executed batch records.
Highlights:
- Vendor documents – Detail which vendor-produced documents and records, critical to product quality and concerning the company’s products/processes, fall under this scope.
- Responsibilities – Establish the distinct responsibilities of QA and CMC throughout the review and approval process.
- Review – Ensure vendor documents and records are thoroughly reviewed by CMC for completeness, technical accuracy, regulatory filing compliance and GMP expectations, and by QA for completeness and GMP adherence.
- Approval – Specify the mechanism by which QA and CMC approvals will be documented and recorded.
4. Batch Record Review and Disposition
Company oversight is crucial for batch release, even at the investigational stage. This SOP establishes a clear chain of responsibility and compliance to ensure proper records are maintained for company-led release of clinical materials.
Highlights:
- Disposition requirements – Align batch disposition process with internal obligations and regulatory guidelines.
- Documents supporting the batch release – Ensure certificates of analysis, master and executed batch records, analytical records, and deviation reports are available.
- Documentation flow and approvals – Define the approval workflow for batch release, including any approvals required from the company.
- Release criteria – Specify acceptable release parameters, including required testing results.
- Deviation handling and impact on disposition – Incorporate steps for handling deviations and their potential effect on product release decisions.
- Statement of Compliance – Issue a formal document attesting a specific batch meets all required specifications, regulatory requirements, and was manufactured in accordance with cGMP.
5. Quality Issues Management
Quality issues (including deviations, complaints, and CAPAs) may arise and, if not properly handled, can compromise patient safety, data integrity, and regulatory compliance. Having a written procedure in place provides a specific, structured framework for how an organization responds to and manages these problems.
Highlights:
- Tracking deviations and investigations – Develop a system for identifying, documenting, and tracking deviations from normal operations.
- Vendor investigations – Ensure the SOP is consistent with the Quality Agreement, defining how vendors report, investigate, and close deviations and quality issues, including all communication and action timelines.
- Risk-based Approach – Establish a risk-based framework for classifying deviations and quality events to prioritize follow-up actions.
- Reporting – Create clear guidelines for who, what, when, and how to report identified quality issues.
- Root cause analysis – Implement processes for performing root cause analysis; without this, a cycle of reactive problem-solving may occur rather than proactive prevention.
- CAPA timelines and tracking – Establish timelines to ensure corrective and preventive actions are implemented in a timely manner.
- Escalation process – Define how major quality issues are escalated internally and externally.
- Effectiveness checks – Establish effective checks for CAPAs by incorporating Key Performance Indicators (e.g., monitoring recurrence within a defined period, trend analysis of similar issues, and quantitative metrics measured before and after CAPA implementation).
6. Change Management
Changes related to the manufacturing process, testing and control of investigational products can impact product safety, identity, strength, purity, and quality. This SOP is designed to identify, evaluate, implement, and document proposed changes to products, processes, or systems. It applies to both internal and external changes at vendors, ensuring all potential effects are thoroughly assessed and mitigated before implementation. Steps and decisions in this SOP can be guided by quality risk management concepts outlined in ICH Q9, Quality Risk Management.
Highlights:
- Change control workflows – Define a clear workflow for initiating, reviewing, and approving changes including those initiated by vendors that require additional company actions.
- Impact and risk assessment for changes – Ensure changes are assessed for potential impact on product quality, safety, and regulatory compliance.
- Approval process – Specify how and when key stakeholders must review and approve changes impacting GMP operations.
- Implementation and verification – Include steps for implementing the change, including a post-implementation review to confirm that the change achieved its intended outcome without causing new problems.
- Notification of stakeholders – Ensure that any change impacting the supply chain or clinical trial is communicated to relevant stakeholders.
- Tracking and documenting changes – Implement systems to ensure that all changes are properly documented and that previous versions of processes are archived.
7. GxP Controlled Documents
Document control is the foundation of any Quality Management System (QMS) in regulated industries. This SOP outlines the entire lifecycle of controlled documents to ensure accurate, approved, and current information is always available to the right people and that obsolete information is removed from use. Controlled documents are critical to regulatory compliance and require a formal system for their creation, review, approval, distribution, revision, storage, and retention.
Highlights:
- Document identification and numbering – Define unique identifiers for each document / document type.
- Author and reviewer responsibilities – Ensure controlled documents are accurate, complete, compliant, and fit for their intended purpose prior to implementation.
- Version control – Ensure document revisions are tracked (i.e., Revision History) and approved according to predefined procedures.
- Establish secure filing systems – Implement physical filing or electronic systems with appropriate security controls.
- Document accessibility – Ensure that necessary personnel can access documents efficiently, even remotely.
- Retention timelines – Set clear retention timeline for various types of documents based on regulatory requirements.
- Archiving and backup – Establish systems for long-term document archiving and disaster recovery.
8. Generating Specifications
Generating specifications from the onset is a critical component to patient safety and regulatory compliance. Specifications set the quality bar for investigational products by ensuring materials are consistent, pure, potent, and free from harmful contaminants. This SOP formalizes how the company will provide input, review, and ultimately approve specifications, even when initially drafted by a vendors.
Highlights:
- Specification management – Define the process for creating, approving, issuing, and revising investigational product (e.g., drug substance, drug product, placebo), raw material, or component specifications, covering instances where they are initiated or revised internally or through vendor collaboration.
- Establishing required content – Specifications should contain a comprehensive list of tests, references to analytical procedures, and appropriate acceptance criteria (numerical limits, ranges, or other qualitative descriptions), along with a unique specification number and detailed change history.
9. Good Documentation Practices (GDP)
Personnel executing activities which are regulated or support GxP activities, must follow the core principle: “If it’s not documented, it didn’t happen.” An effective GDP SOP ensures that all records are complete, accurate, and readily available for review during internal or external audits and regulatory inspections. The rationale for GDP is captured by the acronym ALCOA+, which describes the key attributes of good data: Attributable, Legible, Contemporaneous, Original, and Accurate. The “+” adds further principes: Complete, Consistent, Enduring, Available and Accessible.
Highlights:
- Define core principles – The SOP should be built around the ALCOA+ principles, ensuring records are attributable to the person who made the entry, and are contemporaneous, meaning they are recorded at the time the activity was performed.
- Specify documentation materials – Define the way in which personnel should access current, official GxP documents, as well as approved forms, logbooks, and electronic systems necessary to perform their work.
- Specify tools – Specify the use of permanent, black or blue ink pens only and prohibit the use of pencils, highlighters, felt-tip pens, and other writing instruments that produce smearable or blotting ink.
- Common Scenarios – Provide clear methods for changing or correcting recorded data/information, lining out blank spaces, and provide specific guidance on date/time format.
- Signatures – Define and enforce rules for both handwritten and electronic signatures (if applicable) to ensure all entries are attributable, verifiable, and compliant with regulatory standards.
10. GxP Training
cGMPs emphasize that all personnel performing GxP activities should have the education, experience, and training to perform their assigned duties. This is a fundamental principle of cGMP compliance. This SOP ensures GxP training is performed, documented, and maintained.
Highlights:
- Documentation and accountability – Outline what training is required, who needs to be trained, and how that training is documented.
- Training methods and content – Specify the methods used to deliver training and the content that must be covered.
- GxP Training – Mandate initial and periodic GxP training for all employees performing GxP activities.
- Training files – Establish the required contents of personnel training files, which should include: a job description/job profile, CV/resume, employee signature/initials log, Declaration of Non-Debarment, and completed GxP training forms.
At Syner-G, we specialize in helping virtual pharmaceutical companies get a running start by implementing these 10 foundational CMC SOPs. These procedures establish the cornerstone of a robust, phase-appropriate quality system, giving companies the framework to handle the complexities of early-stage drug development efficiently while prioritizing patient safety and product quality. Adopting this lean, risk-based approach allows companies to focus their limited resources on what matters most: bringing a safe, high-quality investigational product one step closer to patients in need.
