December 1996

Regulatory Notes
Ed Oliver, MSc. - President of CPCS, Inc.

Qualification and Validation of Production Facilities

At the recent CPCS Canadian GMP training course, a question was raised regarding the meaning of the terms IQ & OQ and their applicability in the production environment. Also the issue was raised of what constitutes a validation plan and what it should contain. These questions are indeed relevant to a company's preparation for forthcoming inspections under the 4th Edition of the GMP Guidelines. The Glossary definition defines "Installation Qualification" (IQ) as the "documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed", and "Operational Qualification" as "the documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications."

In this article, we will deal with the initial elements of qualifying a facility, either new or renovated, which is to contain new equipment and/or processes. The validation of products will be dealt with in a subsequent article.

Early this year the Branch issued a memorandum which in essence indicated that the 4th Edition would become effective on January 1, 1997. However inspectors would be judging a company's operations against all aspects of the new guidelines in 1996. Although complete compliance was not expected to be enforced this year it was expected that a company show evidence of preparation for compliance in the new year. In particular, it was mentioned that although Process Validation may not have yet been performed on a company's products it would be expected that a Master Plan for Validation be in preparation.

Sections C.02.004 (Premises), C.02.005 (Equipment), and C.02.011 (Manufacturing Control) of the GMPs have always stated that "design and construction" are elements intrinsic to the set up and production of drug products. The revised interpretations now include the words "qualification" and "validation". This applies not only whether one has an entirely new production facility but also to plant expansions and renovated production areas. Thus all these circumstances demand a plan to enable the qualification of facilities for their appropriateness of design and operation as a fore-runner to the actual product process validations to be subsequently performed.

Even though a company may be in the early stages of its development, it would be wise to set up a validation team as soon as the required component personnel are on board. Such a team will always be needed since no operation will ever be in the state of never needing validation assessments. This group as a minimum should be comprised of representatives from Manufacturing, Engineering, Regulatory Affairs and Quality Assurance. Additions of Upper Management personnel or substitutions with Consultants may be made depending upon a company's circumstances.

The Validation Team will be instrumental in drawing up the "Plan" which will guide the company's efforts in qualifying and validating the facilities, equipment and processes. What would such a plan contain? The following example was used to handle a plant expansion of existing facilities and processes and can be developed into appropriate templates for other circumstances. The Plan contents list would read something along the lines of the following:

Introduction and Plan Approvals

Facility Qualification Plan

The "Plan Approach" is fundamental to ensuring that everyone is on board and knows what must be covered to complete the plan. It will detail why the qualification is being carried out; who will be responsible for implementing and approving all aspects of the plan; how the protocols will be generated; the acceptance criteria; the calibrations to be performed and according to what standards; the documentation and approvals of deviations; and an estimated completion date.

The "Scope" defines what is to be included in the total evaluation and what products are to be included in the overall framework.

The "Staffing and Manpower" defines the assignments of key individuals and their responsibilities, together with organization charts and resumes.

The "Facility Scope" details the present facility design and how the new expansion is intended to be integrated into the overall enlarged facility, a general strategy of how the construction work is to be performed adjacent to existing operations and how they will eventually be combined with new equipment installations etc. Flow diagrams of existing and future intended operations would include production plant, equipment location, material and personnel movements, and HVAC zones.

The "Process Description" details the product operations to be performed in the new and combined areas, together with process flow charts.

The "Equipment and facility Descriptions" detail the new equipment to be installed or movement of existing equipment to new locations.

The "Process Validation" details the processes that are to be eventually validated or revalidated in the new area designations, giving information on scale-up criteria and batch sizes.

The "Process for Area Combination" details how the changeover is to be effected to ensure the integrity of existing and on-going manufacturing processes.

The "List of Appendices " details the elements to be included in this section, such as, organization charts, resumes of responsible officials, a list of SOPs applicable to the plan, examples of protocols, and any plan amendments.

It is in the Facility Qualification Plan, that more significant details are given, such as:

With an approved and written plan in place and ready for use, the overall process of implementation is understood by all concerned in ensuring its success. Furthermore it is positive documented evidence to the inspector that the company knows what it is doing, and that it recognizes and intends to fulfil its obligation to "design and construct" for assurance of compliance.