Validation batch preparation

Document checklist. All documents that should be examined and in proper order prior to the initiation of the validation batches are listed. They are checked for availability and accuracy. Preparation of batches should not commence unless these documents are finalized and signed. An example is shown below ... 

Analytical methods for assay of the toxicology formulations and cleaning validation are developed and validated in preparation for the first GLP studies. Release and stability testing of the toxicology test articles are performed to support the suitability of the materials through their anticipated period of use. Typically, short-term accelerated stability studies are performed on the toxicology batches for at least 3 months to cover the time from date of manufacture through the last dose. 

Hence, it is important to ensure that sufficient validation/QC samples are prepared to cover all of the expected validation batches and, if possible, the study sample analysis batches also. For commercial QC material, this means obtaining sufficient material from the same manufacturer s lot number. Clearly, stability or shelf life may limit how long this material may be stored and used. 

Five validation batches for a simple process, optimized and validated at the pilot scale could be considered by some to be an excessive number. An alternative approach would be to prepare two batches with the standard process. The protocol would then state that if the batch 1 were satisfactory the next batch would challenge... 

Small-molecule manufacturing is also a system of checks and balances in which any small increase or decrease in reaction step performance can have consequences downstream. As always, patient safety is of utmost concern. Any manufacturing process changes that alter an impurity level or introduce a new impurity, even as low as 0.1%, may necessitate additional toxicity studies and documentation for review and registration. In addition, an improvement in reaction efficiency may alter bulk product crystallinity or polymorph composition that can affect formulation and human pharmacokinetics. Once process parameters are finalized, the ultimate manufacturing step involves selection of a manufacturing site, transfer of the process, and preparation of a demonstration batch followed by a minimum of three consecutive validation batches of API to demonstrate that the synthesis of material can be controlled within analytical specifications and reproducibility. 

Stock preparations are performed according to a standardised preparation instruction, an instruction that has been validated prior to use. This is called a Batch Preparation Instruction (BPI). Also for extemporaneous preparations, a standardised preparation instmction - a BPI - is preferred. However, often the operator has to follow a non-standardised preparation instmction that is less extensive, where no prior validations have been performed, see further Sect. 33.5. 

When all components of a preparation process are qualified and validated separately, the largest part of the validation process is complete. The prerequisites are described in a protocol and test plans for the final validation are enclosed. In general process validation includes preparation of three consecutive batches with extended sampling. Acceptance criteria typically include no OOS, no OOT and critical IPC within specified limits. Samples may be collected fi om critical control points during the manufacmre. However, when unit operations have been validated, often only samples of the finished product (after packaging and labelling) are tested. A conclusion about the preparation process as a whole is reported in a Validation report, which has to be approved by the heads of Production, QC and Q A and afterwards will be a base for change control in relation to the process. 

An important part of the retrospective validation is the collection of all batch preparation and analysis records of the preparations in the period examined. This is done in a systematic way by ascertaining that all preparations are performed in accordance with the applicable procedures and instructions, all in-process controls met the requirements and all discrepancies (e.g. less yield than normal) are adequately explained. All preliminary and final analytical results are taken from the analysis records. To support the data collected the analytical validation is used. 

In cases where test pieces (or items) are prepared, the issue of obtaining a homogeneous batch of items is even more complex. Here the preparation procedure sets limits, in combination with the properties to be certified. The uncertainty of the property values should appreciate this fact, as otherwise the uncertainty of the reference material is only valid for the batch, not for a single item from the batch. This... 

Documentation comprises procedures, instructions, test methods,batch records, and so on that are documented and controlled. Documentation is prepared, reviewed, and approved by qualified personnel. Approved copies of documents are distributed to relevant departments and superseded copies are retrieved and archived. The retention period for each type of document is specified. Documents are issued with document and version numbers for ease of identification and reference. Master copies of documents are filed at secured locations with authorized access. Master copies stored in electronic media require validation in accordance with FDA regulation 21 CFR Part 11 (see Section 9.6.3) to assess the security of access and data integrity. Operators are trained and retrained to only apply the latest approved documents. 

No other papers have considered carefully the effects of catalyst particle size on activity. Comparisons of catalysts with different particle sizes could be misleading. Fortunately, most investigators have used a single batch of chloromethylated polystyrene to prepare their catalysts, and the subsequent comparisons of activities with different active site structures are likely valid. 

ABC Pharmaceutical Industries information. The equipment preparation pages of the master batch record specify the validated sterilization processes to be employed in the preparation of the equipment for (product name) USP. Cycle sterilization parameters are defined along with attributes such as loading patterns and the mechanics of operating the sterilizing equipment. The following lists the sterilization cycles utilized for the equipment required in the processing of (provide product name) USP ... 

The most accepted validation method is prospective. This validation approach relies on completion of the validation before commercial production begins and requires the manufacture of at least three consecutive batches during protocol execution. The batches are evaluated for conformance to the protocol requirements a report is prepared and approved. Then the lots are released for sale and production commences using the validated process. For excipient manufacture, where the material has been produced for quite some time, this approach is usually inappropriate. 

In practice, usually two or three pilot-production (100 x) batches are prepared for validation purposes. The first batch to be included in the sequence... 

A written protocol that describes what is to be accomplished should be prepared [5], It should specify the data to be collected, the number of batches to be included in the study, and how the data, once assembled, will be treated for relevance. The criteria for acceptable results should be described. The date of approval of the protocol by the validation organization should also be noted. The value of a protocol is to control the direction of the study, as well as provide a baseline in the event unanticipated developments necessitate a change in strategy. A written protocol is also an FDA recommendation [1],... 

For example, most companies would rather reference their supporting documents than have FDA ask whether or not a particular document exists. Further, this practice will assure that the company has actually taken sufficient time and prepared the document referenced. There are those companies that prefer to voluntarily attach the documents rather than just reference them. This may not be in the best interest of CGMP manufacturers for two clear reasons. First, attaching every development report, every batch record, every analytical method, every support protocol/report and so forth will make a process validation document—a hefty document to begin with—too big to read. Second, volunteering any information is considered very dangerous, as it is very rare for a company to have no dirty laundry. Why hang it out for FDA or any audience to see ... 

Labeling. The labeling section simply discusses how labels will be prepared and with what information. Typically the batch number, the validation document number, the validation sequence or event number (run x of y), the sample number (or other descriptive information e.g., sample type and/or time), and of course the date that sampling occurred are recorded on a validation label. 

The validation protocol should be prepared after the master batch record is approved and signed by responsible parties (i.e., the manufacturer and NDA or ANDA holder). The batch directions should be detailed and easily understood. For example, mixing speeds and times, mixer positions, and method of adding ingredients should be explained clearly. The protocol must agree in process descriptions and flowcharts and be specific enough to remove any ambiguities on process conditions, decisions, or product specifications. For these reasons, it is usually beneficial to prepare a production-sized, prevalidation batch with the proposed final batch record. This batch should also be completely tested and meet finished product specifications. 

Preparation and analytical batches must be clearly identified with a unique number in laboratory bench sheets, notebooks, and computer systems. The same applies to QC check samples associated with each batch. During data quality assessment, the data user will determine the quality of the field sample data based in the results of the batch QC check samples that are part of the preparation and analytical batches. The data user will examine batch QC check samples first and, if they are acceptable, will proceed to individual sample QC checks. A complete examination of these QC checks will enable the data user to evaluate the quantitative DQIs (accuracy and precision). A combination of acceptable batch QC checks and individual QC checks makes the data valid on condition that the qualitative DQIs (representativeness and comparability) are also acceptable. 

---