Introduction
This guidance is to address environmental control for existing, new, and modified non-sterile API processing areas used for the manufacture of commercial materials. This includes non-sterile API manufacturing areas where the API will subsequently be used to produce sterile Drug Product.
Sterile and aseptic API manufacturing areas are outside the scope of this guidance.
This guidance applies to those areas where the API molecule is formed and subsequent manufacturing steps. In accordance with ICH Q7a, it is expected that there be increasing environmental control from the early steps of the API manufacturing process (e.g., from the introduction of the API starting material for small molecule chemical synthesis), through to the final API steps.
Recommendations and Discussion
Environmental Control Risk Assessment
For each API product, a risk-based assessment of environmental control requirements should be performed, documented, and approved by the Site Quality and Production Teams.
The risk assessment may be conducted on a product or facility-centric basis. This risk assessment should include consideration of at least the following:
Type of API manufactured (e.g., small molecule API via chemical synthesis or classical fermentation);
For APIs produced by chemical synthesis or classical fermentation, the risk assessment should be conducted to include the step where the API molecule is formed and on each of the subsequent step(s) of manufacture, including an evaluation on whether or not there is further purification of the API;
For APIs exposed to the environment, the subsequent Drug Product dosage form (e.g., oral, parenteral, topical, inhalant) should be considered during the risk assessment. For APIs subsequently used in multiple dosage forms, it is recommended that the most conservative dosage form with respect to patient safety (e.g., parenteral) is considered in the risk assessment;
Microbial risk associated with the API process (e.g., high water activity, water-wet cake for Final API, inhibitory nature of the process for microbial growth), that may have an effect on the bioburden of the drug product;
Risk of microbiological contamination of Intermediates and APIs, that have an established microbiological limit (e.g. from gowning, sanitization practices or open drains);
The extent of exposure of the final API to the surrounding environment (if any);
The extent of exposure of API product contact Packaging Materials to the environment, if any; and
Dedicated versus multipurpose production areas/facilities and the risk of potential Cross Contamination.
The risk assessment should be documented and include rationales and conclusions. The documentation may be in one of several forms (e.g., validation plan, protocol, separate evaluation/rationale document, system level impact assessment). The assessment results and conclusions should be approved by Site Production Team and Quality Team.
Environmental Control Strategy
Final API steps include where the API molecule is formed and any subsequent manufacturing steps where there is no further purification of the API. The environmental control strategy for these areas should include consideration of the following:
Design of the applicable API areas to meet the criteria for the drug product manufacturing area where the API is first exposed in drug product manufacturing [e.g., design of these API areas to meet the comparable ISO 14644 Non-Viable Particulate levels];
Temperature and humidity requirements, where specified for the product;
Potential for microbial contamination from the environment, if critical to product quality;
Pressure Differentials between adjacent areas to avoid contamination of the API product;
Cleaning, and where applicable Sanitization, of product contact Facilities;
Equipment surfaces;
Personnel practices (e.g., gowning/de-gowning and training) and
Other product specific requirements as applicable (e.g. sensitivity to light).
If API, API-product-contact packaging materials, or clean product-contact equipment are exposed to an environment, protective measures should be implemented or the environment should be controlled to eliminate or reduce the exposure to the environment. The protective measures can include consideration of the following:
Protection of product contact packaging materials (e.g., drum liners, super-sacks) from the environment (e.g., keeping them covered);
Protection of product contact equipment from the environment (e.g., by keeping equipment closed or covered);
Elimination or reduction of the exposure to the environment (e.g., with use of continuous liners or down-flow booths); and
Control of the environmental area to minimize the potential for contamination (e.g. enclosed rooms or booths with pressure differential).
For APIs exposed to the environment, the following facility design characteristics should be considered when evaluating the risk of impact on the API product:
Potential contributors of viable and non-viable contamination (e.g., water, compressed gas systems, material of construction for product contact surfaces, architectural finish, sinks and floor drains);
HVAC air quality, room pressurization and access arrangements, material and equipment storage;
Personnel and material flows.
Room/area control strategy for Pressure Differentials, for areas where API products are exposed to the environment should be specified and documented, along with rationales.
Where determined to be critical, room/area pressure differentials should be controlled, monitored, and recorded. There should also be indication of function and failure (e.g., alarms) for critical pressure differentials.
When APIs are exposed to the environment, considerations for determining if temperature and humidity controls are critical to product quality should include:
Product hygroscopicity;
Product sensitivity to temperature and humidity;
Product Specifications;
Preclusion of condensate on room surfaces;
Additional considerations such as operator comfort and equipment operation; and
For Exposed APIs where humidity and/or temperature are determined to be critical, the temperature and/or humidity should be controlled, monitored, and recorded. There should also be indication of function and failure (e.g., alarms) for these critical parameters. Where applicable, humidity and temperature control and indication should include action conditions reflective of the requirements of the product. The frequency of monitoring, data reporting requirements, and action condition limits should be defined and approved by Site Quality and Production Teams.
If environmental control is required, based on the risk assessment, the elements of the control program can be described in Site documentation [e.g., a Site Standard Operating Procedure (SOP) or plan]. This documentation should be approved by the Site Quality Team and the Site Production Team.
For manufacturing processes and/or areas determined to be of high risk for contamination based on the risk assessment, environmental baseline testing and routine environmental monitoring for new and existing facilities should be considered. Further information on establishing baseline testing and routine monitoring will be outlined in a separate guidance.