Quality systems

GMP quality system. In early development, relationships between material attributes, process parameters and product quality attributes are typically not well understood. It should be anticipated that even during GMP manufacture, there will likely be a need to deviate from the process conditions specified in a batch record. Quality systems should have the flexibility to allow these changes to be documented in batch records without formal prior approval from the Quality department. However, these changes should be reviewed by Quality after production, to assess the potential impact to product quality and patient safety. It is crucial to summarize and track process changes because much of this information will be used to develop process understanding and may be included in development history reports. In a similar manner, unplanned deviations from the written manufacturing procedures should be documented and justified, but may not need to be addressed in a formal corrective and preventive action (CAPA) system, because the process is changing continuously as part of the development process. Unplanned deviations that are likely to impact product quality and patient safety, such as cleaning failures, contaminations, and certain equipment failures must be investigated and corrective actions put in place to prevent recurrence.

Risk management in early development. To assist in the application of risk-based decision making in the development and manufacturing of drug product, the authors recommend that companies apply a scientific and risk-based approach, similar in principle to that of the ICH Q9 Quality Risk Management guideline (7). Annex I of the guideline describes various methods and tools that can be useful to determine the relative risks related to system risks, such as facility and people; organizations (including quality systems); process risks and product risks (safety and efficacy). There are many ways of identifying, qualifying, and mitigating operational and quality risks. Regardless of the methodology used, a documented strategy and good records of risk-based decisions are important in ensuring that the appropriate factors are considered for the protection of patients and product quality.

Regardless of the scale of manufacturing, the facility used for manufacturing clinical trial supplies must meet the basic GMP requirements as described in the regulations and guidance documents. Below are three scenarios for early development and the advantages of each as pertaining to early development. The first involves a pilot plant facility designed and equipped for routine GMP operations. The second scenario aims to establish a GMP area within a laboratory environment. The third example focuses on conducting GMP manufacturing or leveraging the practice of pharmacy in close proximity to the clinical site.

GMP facility for drug-product manufacture. The traditional approach in GMP drug-product manufacture is to use a dedicated facility (often called a pilot plant) for early phase clinical trials. Advantages of this approach include that the quality systems for the facility (i.e., maintenance, calibration, cleaning, change management, CAPA, and documentation) are well defined, and that training and other activities required for maintaining GMP compliance are centralized. Other drivers to use a pilot plant in early development may be the need for specialized equipment, or larger batch sizes in special situations.

GMP area within a laboratory setting. In some cases, it may be advantageous to establish a GMP area within a "laboratory setting" (i.e., a drug-development facility not dedicated to the production of clinical supplies) for the manufacture of drug product in early development. The rationale for this approach might be to avoid the significant investment in setting up a dedicated facility and to create simpler, more flexible systems that meet GMP requirements but are tailored for the specific activity envisioned. Examples where this approach might be considered include the need for special containment not available in the pilot-plant; the need to work with radioactive or hazardous materials, use of controlled substances and the production of "one-off manufactured" product used for proof of concept. The business rationale should be documented and approved by the manufacturing and Quality groups. As long as the appropriate GMP controls are maintained, especially as related to operator safety, cleaning, and prevention of cross-contamination, there is no compliance barrier to using "lab-type" facilities for the manufacturing of early phase clinical batches. Before GMP manufacturing is initiated, however, a risk assessment should be conducted and documented. Inclusion of representatives from Quality, analytical, clinical manufacturing, product development, and environmental health and safety would be prudent. When selecting/designing an early development clinical manufacturing facility, consideration should be made for the receipt, storage, dispensing, and movement of materials. The manufacturing processes in the nondedicated area must protect the product, patient, and the manufacturing operators.