In an ideal world, validation would begin with parallel product research and development activities. Validation for lyophilized products occurs more often during scale-up to manufacturing. Under growing regulatory pressure and the realization of the greater benefts, however, validation activities are being under- taken while the product is along the development pathway. There are also circumstances in which validation is required for existing commercial products, either because of changes requiring additional study or to meet current regulatory stan- dards. This chapter will approach validation as an integral part of developing a new product. Appropriate application of the principles discussed may be applied for either a change control procedure or for revalidation, based upon specifc needs.
34.2 PREPARING FOR VALIDATION
Components of a comprehensive validation program include equipment qualifcation (EQ), process engineering and pro- cess validation. The EQ portion focuses on the lyophilization equipment, including semiautomated or automated loading and unloading equipment, and is valid for processing the par- ticular product or, for a multiproduct operation, any number of products. Conversely, the process for each product is unique and applies only to one product, and therefore the process validation is specifc to that product.
The experience gained and data compiled during develop- ment are a signifcant part of the scientifc rationale that forms the basis of validation studies. It also provides a critical reference for integrating a product into a production environment. This saves on adjustments to the process and further development studies at the time scale-up and validation is attempted in manu- facturing. Completing process studies at both the ideal target parameters as well as boundaries of the process parameter range results in greater safety and effciency in the parameters and a more robust process. Establishing a proven acceptable range (PAR), frst introduced in 1984 by Chapman, is recognized as a “best practice” as part of lyophilization process engineering (1).
Activities for validation of a “legacy” product where devel- opment and initial validation may not meet current industry practices requires constructing a historically based fle. Data such as pre-formulation, product and process development may not be available with historical manufacturing experi- ence for the commercial product manufacturing. The most challenging task in this instance is justifcation for the product formulation and process design. This is particularly diffcult in circumstances with commercial products that were devel- oped prior to the awareness of the benefts of validation.
When a new product is in the development phase, a com- prehensive report that includes technology transfer for Phase III clinical trial material should be assembled prior to scale-up and technology transfer to manufacturing. This report addresses the starting raw materials, including the drug substance, excipients and packaging components, along with formulation, compound- ing methods, dosage information and lyophilization process engineering activities. Each facet of product manufacturing needs to be included, beginning with testing of the product com- ponents through processing and fnal packaging requirements. The fnished product qualities must also be defned. The report should clearly explain the scientifc rationale and justifcation for the formulation and manufacturing procedures.
This development report is a crucial reference for integrat- ing a new product into a manufacturing operation. The accep- tance criteria for any validation study are based upon product and process requirements outlined in the development report. The report provides an invaluable reference for technology transfer, change control program management and trouble- shooting during routine manufacturing.
EQ is best considered at the time of equipment specifcation and selection. The advantages include more effective project management, ease of completing the validation package and speed of bringing the equipment online. Equipment requirements and performance are based upon the processing parameters nec- essary for manufacturing the product, as identifed during pro- cessing engineering studies completed during development.
As with the specifcation and purchase of any new piece of equipment, well-written equipment specifcations include the intended validation activities for qualifying the equipment and assuring it meets the processing requirements. Defning testing and documentation expected during the Factory Acceptance Testing (FAT) at the vendor’s facility is also a useful contractual agreement.
34.3 SOURCES OF INFORMATION
Sources of information include the Research and Development, Engineering, Clinical Supplies Manufacturing, Quality Control, and Regulatory Affairs groups. A development report is a key source of technical information regarding the characteristics of the active pharmaceutical ingredient (API), product and formulation design, and product processing requirements. The physiochemical character of the active sub- stance, if appropriate, along with the functions of the excipi- ents of the fnal product formulation and liquid and solid-state stability data are critical parts of such a report. Process devel- opment data and fnished product characteristics should be available within the development report. Specifc information on the equipment design and performance for the EQ is often archived by the Engineering and/or Validation department. Other engineering references include maintenance and cali- bration procedures. Operating procedures covering product handling and operation of the lyophilizer are available within manufacturing documentation. These would include the unique aspects for processing lyophilized fll volume frequen- cies and tolerances and operation. Finished product testing methods for the active ingredient, reconstitution and residual moisture should be available from the development scientists, Analytical Development group as standard testing methods for use within Quality Control. The Regulatory Affairs staff should be consulted for commitments made in regulatory flings and communications to regulatory agencies.
34.4 RECOMMENDATIONS FOR A VALIDATION PROTOCOL
The differing circumstances under which a validation study is prompted often dictate the best approach. Agreeably, prospec- tive validation, where the validation studies are all completed and approved prior to shipment of any product, is preferred. There are, however, opportunities to complete certain valida- tion studies during preparing material for Phase III clinical studies in which the product is to be administered to patients. Here, validation is concurrent with producing these materi- als. In addition, when implementing validation studies on an existing marketed product to bring the operation up to current regulatory expectations, concurrent validation would also be appropriate. Retrospective validation would be applied to a review of historical data of an existing process and product. Examples would be the review of the lyophilization process- ing data, fnished product batch release test data and stability data from the commercial stability testing program.
The design of the validation testing and the composition of the protocol refect the circumstance under which the study is conducted. For retrospective validation, the “test” may be sta- tistical analysis of batch release data such as assay, pH, physi- cal appearance, residual moisture, reconstitution time and constituted solution appearance. This retrospective process validation would be intended to show that the process is within an adequate level of control and the product is of consistent quality. A critical review of the processing conditions in a ret- rospective validation may consist of a test comparing actual processing conditions during lyophilization to ideal param- eters, showing not only adherence to the defned processing conditions but also demonstrating process reproducibility.
Concurrent validation studies may be used during clinical manufacturing and scale-up activities. Additional testing or an increased number of samples, as in the case of transferring a product to another site or manufacturing material in a new production lyophilizer, may be conducted as a concurrent vali- dation study. This would be reasonable if the parameters have not changed and the process has already been adequately vali- dated. In addition to fnished product testing, short-term accel- erated stability may be appropriate prior to actually releasing the batch for distribution. Long-term stability studies should be done at the recommended storage conditions, up to and including at least six months beyond the desired expiry date.
Although there are circumstances in which retrospective or concurrent validation may be appropriate, prospective valida- tion is preferred. This entails the testing, review of the data and approval of the completed validation studies prior to releasing product for distribution and use. Identifying the target process parameters and a proven acceptable parameter range, along with demonstrating consistent product quality and stability would be highly desirable prior to introducing the product into a manufacturing environment. It could also decrease the amount of time necessary for getting a new product to market.
Numerous studies to support process validation can be com- pleted during the development phase. These studies correlate the product formulation, presentation and lyophilization processing parameters with fnished product attributes and long-term sta- bility. In addition, the reproducibility of the process would be demonstrated along with the consistency of fnished product attributes. Uniformity studies during the frst batches being inte- grated into manufacturing are often the last leg in the sequence of validation studies for bringing a product to market. Depending on the supporting data available from development studies, lim- ited or short-term accelerated stability may be suffcient.
34.5 PREPARATION OF THE PROTOCOL AND SOPS
Each activity performed as part of the Installation Qualifcation (IQ) and Operational Qualifcation (OQ) should be orga- nized into discrete functions and documents. During the IQ, the review and verifcation of utility connections, piping of the refrigeration and heat transfer system, reconnecting the vacuum system, rewiring of the control system, start-up and testing may be organized into a distinct document for each activity. This “modular” approach becomes more effective and effcient as the complexity of the procedures and equip- ment increases. Each aspect of bringing a lyophilizer online or integrating a new product into a manufacturing environ- ment often involves a number of individuals or departments. Arranging the overall effort into smaller packages correlat- ing with distinct activities makes the communication between individuals and departments more manageable. For example, the project engineer responsible for installation of a new lyophilizer may use a mechanical contractor to reconnect the piping and connect the utilities and an electrical contractor to connect the control system wiring. In such a case, a docu- mentation package covering each activity may be issued and completed for each part of the project involving each contrac- tor. A documentation package organized in such a manner is also a useful tool for project management.
Such an approach is also applicable for product and pro- cess validation. Considering the ranges of formulation aspects such as the acceptable pH range, a focused study to correlate the pH, phase transition temperature and fnished product aspects upon processing would be well suited as a distinct protocol. This protocol may parallel studies already conducted during development. Another example is establish- ing the PAR for the processing parameters. Identifying such ranges is accomplished by processing at extreme shelf tem- peratures, chamber pressures and times, following the PAR approach as referenced earlier.
34.5.1 estABlishinG AccePtAnce criteriA
The selection of acceptance criteria is dependent upon the circumstances under which validation is being under- taken and requires judicious consideration. Challenges to the equipment, for example, may depend upon whether the lyophilizer is being frst installed or whether validation is being completed for an existing unit currently in use. Where the lyophilizer is new, the acceptance criteria based upon the performance requirements that are identifed within the equipment specifcations would be warranted. The advan- tage of acceptance criteria based upon the stated equipment capabilities is that any process that is within the performance capabilities of the equipment could be utilized for lyophi- lizing product. For testing an existing unit in production, however, the most rigorous processing conditions would be a justifable test challenge. The jeopardy of test challenges based upon the most current processing conditions is that if a process for a new product is outside of the parameters tested, then additional testing or qualifcation at the new parameters would be necessary. Details of constructing validation pro- tocols, designing studies and establishing acceptance criteria will be presented in each respective section of this chapter. In approaching validation, it is more important to test and docu- ment what is critical for gaining a high degree of confdence that the process is well-defned and reproducible, the proce- dures are adequate and appropriate, the equipment is suitable for completing the process and the product is of consistent quality, purity and stability. In addition, it is a valuable oppor- tunity to collect useful information for supporting a change control program. Validating for the sake of simply document- ing information in a protocol, not having a clear understand- ing of what is signifcant, or creating a voluminous collection of data because more is better should be avoided. As a general rule, do what is necessary and do it well!
For some studies, as in the OQ, references will be made to known performance capabilities of the equipment. These are intended to be examples rather than standards. A few general notes are, however, appropriate. Most importantly, selecting acceptance criteria needs to be based upon a justifable scientifc rationale. This is applicable whether qualifying an existing piece of equipment for commercial product manufacture or validating a process during clini- cal manufacturing. Selecting appropriate processing ranges to be encompassed within the validation has a signifcant long-term effect in manufacturing. For example, when the range of residual moisture correlated with suitable stabil- ity is adequately determined during development, then any batch in manufacturing exhibiting a moisture within the boundaries of that range would be acceptable. If there were a batch where the residual moisture was beyond the bound- ary, then there would be reasonable questions whether that batch should be released. Adopting such a philosophy pro- vides a clear and reasonable approach for successful routine manufacturing of high-quality product. There is also little question when a batch is found to be outside the PAR. This eliminates the scenario of placing a batch on stability or doing additional testing when there is a question of what a suitable envelope of processing conditions or product qual- ity aspect would be for a batch to be released. Establishing a PAR, or PAR approach, becomes a valuable asset in a manu- facturing environment.