| Validation | | | | achieve that goal, and the acceptance criteria. It is an |
| Validation is required to ensure that a process, | | | | FDA expectation that all validation protocols be |
| system, material, method, product, piece of | | | | approved before execution. Typical sources for |
| equipment, or personnel practice, will meet its | | | | approval are the department responsible for protocol |
| intended purpose and function or allow functioning in | | | | preparation, the department where the equipment |
| a reliable, consistent manner. A firm derives little | | | | will be installed and the quality group. |
| benefit if a thorough understanding of validation | | | | Protocol & Acceptance Criteria |
| remains solely within the validation department. | | | | Product quality attributes must be detailed in the |
| After four decades of existence, validation is little | | | | protocol. "Acceptance Criteria" are often the |
| better understood now than when it was first | | | | established Product Specifications. Validation should |
| conceived--beyond the concept of "requiring a | | | | not be used to establish or optimize processing |
| minimum of three runs". The term "validation" may | | | | parameters and specifications. Acceptance Criteria |
| differ in meaning from company to company. | | | | may be more stringent, but should never be less |
| Validation is demonstrating and documenting that | | | | demanding, than the Product Specifications. Watch |
| something does (or is) what it is purported to do (or | | | | for subjective statements, since they cannot be |
| be). | | | | validated. Example: ...continue to add water until you |
| Challenge of the Auditor's Role | | | | have a suitable granulation..." |
| Resources to support validation may not be the best | | | | Test conditions should encompass upper and lower |
| for adhering to compliance procedures. Start by | | | | processing limits which place the most stress on the |
| understanding the SOPs pertinent to validation and, | | | | system. Key process variables should be monitored |
| specifically, process validation. The auditor's role will | | | | and documented. Data analysis should establish |
| be to examine executed protocols and reports | | | | variability of process parameters. |
| against internal SOPs and external regulations. In | | | | FDA's Perception of the Role of the Quality Unit |
| addition to the SOPs governing Process Validation, | | | | Those involved in validation must understand what |
| the auditor needs to know if there have been other | | | | responsibilities the FDA holds the quality unit |
| commitments against which a process validation | | | | accountable for. Ensure that any additional |
| should be checked.o Prior internal audit | | | | requirements from the quality unit have been met by |
| commitmentso Customer audit commitmentso | | | | the executed validation--especially additional testing, |
| Internal program initiative commitments (e.g., GMP | | | | repeating questionable tests, and providing more |
| Program)o FDA commitments (filing or inspection) | | | | rationale. |
| When are Process Validations (or Revalidations) | | | | FDA Regulations for sampling and testing are included |
| Required? | | | | Part 211--Current Good Manufacturing Practice for |
| During R&D, physical and chemical performance | | | | Finished Pharmaceuticals, Subpart F--Production and |
| characteristics should be defined and translated into | | | | Process Controls, Section 211.110 Sampling and testing |
| specifications, including acceptable ranges, which | | | | of in-process materials and drug products |
| should be expressed in measurable terms. The validity | | | | In part, these regulations require that written |
| of such specifications is verified through testing and | | | | procedures shall be established and followed that |
| challenge during development and initial production. | | | | describe the in-process controls, and tests, or |
| Validation of such processes need not be done | | | | examinations to be conducted on appropriate |
| before the Regulatory Filing (i.e., NDA, ANDA. | | | | samples of in-process materials of each batch. Such |
| Validation commitments may be included in the | | | | control procedures shall be established to monitor the |
| regulatory filing. The Validation Master Plan should | | | | output and to validate the performance of those |
| include a periodicity (e.g., bi-annual) and specify | | | | manufacturing processes that may be responsible for |
| revalidation when equipment, or other pertinent | | | | causing variability in the characteristics of in-process |
| element, changes. When Annual Process Review | | | | material and the drug product. Such control |
| (APR) indicates that "drift" is occurring, revalidation | | | | procedures shall include, but are not limited to, the |
| must be done. | | | | following, where appropriate: tablet or capsule weight |
| FDA Regulations for process controls are included in | | | | variation; disintegration time; adequacy of mixing to |
| Part 211--Current Good Manufacturing Practice for | | | | assure uniformity and homogeneity; dissolution time |
| Finished Pharmaceuticals , Subpart F--Production and | | | | and rate; clarity, completeness, or pH of solutions. |
| Process Controls , Section 211.100 Written | | | | Failure to Meet Acceptance Criteria |
| procedures; deviations. | | | | Unless the acceptance criteria are met, or there is a |
| In part, these regulations require written procedures | | | | sound justification for not meeting them, the goal is |
| for production and process control designed to | | | | not achieved and the validation has failed. When |
| assure that the drug products have the identity, | | | | protocol failure occurs, it is customary to conduct an |
| strength, quality, and purity they purport or are | | | | investigation. The investigation should: identify the |
| represented to possess. These written procedures, | | | | assignable cause, identify corrective actions, and |
| including any changes, shall be drafted, reviewed, and | | | | restart the activity. The importance of this |
| approved by the appropriate organizational units and | | | | investigation and identification of corrective actions |
| reviewed and approved by the quality control unit. | | | | cannot be overstressed. If the investigation does not |
| Written production and process control procedures | | | | identify an assignable cause for the failure, the |
| shall be followed in the execution of the various | | | | validation must be restarted. |
| production and process control functions and shall be | | | | Validating a Transferred Process |
| documented at the time of performance. Any | | | | In the age of multi-national corporations, it is not |
| deviation from the written procedures shall be | | | | uncommon for an R&D unit to be located in one |
| recorded and justified. | | | | part of the nation (or globe) and the manufacturing |
| Validation Types | | | | unit in another. Thus, when a process is transferred |
| There are several different types of validation | | | | from one place to another, a number of technology |
| approaches. The best is "Propsective", since it is | | | | transfer points and documents are generated as |
| planned for and is, therefore, most favored by the | | | | prospective validation in order to proceed with |
| FDA.oRetrospective:assesses historical performance; | | | | validation through the various steps of product |
| traditionally requires more data, not permitted at | | | | development. There are many departments involved |
| some companies, but may be necessary for products | | | | and they are usually isolated units. Confusion results |
| that have been in production for a long time and | | | | unless communication is good. Often, a project |
| pre-dated current requirements for | | | | management team approach will facilitate inclusion of |
| validation.oConcurrent:gathers data as runs are | | | | all affected units and identification of all of the steps |
| executed; less than ideal due to lack of | | | | involved. |
| pre-planningoProspective:planned protocol, | | | | Validation of Transferred Technology |
| pre-validation tasks ensured; FDA-favored | | | | Audit checklists can be used to ensure that important |
| Process Validations (Process Qualifications) | | | | elements of the transferred process were not |
| Process validation is establishing documented | | | | overlooked or misunderstood. Appropriate participants |
| evidence which provides a high degree of assurance | | | | should have approved the protocol and also the final |
| that a specific process will consistently produce a | | | | report. If it isn't clear to the auditor, it won't be clear |
| product meeting its pre-determined specifications and | | | | to FDA. |
| quality characteristics. The intent is to demonstrate | | | | Questions Often Asked During Technology Transfer |
| that a process repeatedly yields product of | | | | Raw Materials |
| acceptable quality. A minimum of 3 consecutively | | | | Do specifications exist? |
| successful cycles--on a given piece of equipment | | | | Do they make sense? |
| using a specific process--constitutes process and | | | | Are the test methods reliable? |
| equipment validation. Not only is the process under | | | | Are the specifications needed? |
| scrutiny, but the piece of equipment used to deliver | | | | What should be specified but isn't? |
| that process is as well. Process operating limits should | | | | What is the source of raw materials? |
| be tested, but not edge of failure. "Robustness" and | | | | Are there more sources? |
| "worst case" are common goals. | | | | What is the grade to be used? |
| Activities that Occur in Advance of Process Validation | | | | Are the grades interchangeable? |
| Analytical methods must be validated. Processing | | | | Equipment |
| parameters and conditions must be specified and | | | | Does the plant have the proper equipment? |
| approved. There must be an availability of clear and | | | | Are the batch size and equipment matched? |
| detailed SOPs and Manufacturing Batch instruction | | | | Does an alternate supplier exist? |
| which avoid the use of subjective criteria and wide | | | | Can the equipment in the plant be used--even though |
| processing ranges (e.g., mix gently for 10 - 60 | | | | the principle of operation is not yet specified? |
| minutes). | | | | Process Parameters |
| Upstream Tasks to Minimize Variability | | | | Are the set points too narrow? |
| Check to ensure that tasks are completed which | | | | Are the set points too wide? |
| could add variability to the validation, such as: | | | | How were the set points determined? |
| -Employee training | | | | Sampling |
| -Equipment IQ, OQ, Calibration & Maintenance | | | | How do I sample? |
| -Component specifications | | | | What do I sample? |
| -Environmental requirements (temperature, humidity, | | | | Where do I sample? |
| controlled air quality) | | | | Why should I sample? |
| -Qualification of key production materials | | | | How much sample should I take? |
| Importance of the Protocol | | | | What does the data mean after it is obtained? |
| It is a commitment established by the parties | | | | Final Product |
| involved with the activity. It involves a description of | | | | How were the specifications set? |
| the activity, the proposed and agreed-upon manner | | | | Are the tests reliable? |
| to achieve that goal, the number of runs required to | | | | |