To Prepare or Not To Prepare - There is No Question - - BioPharm International


To Prepare or Not To Prepare - There is No Question

BioPharm International

Batch Records The biopharmaceutical industry generates massive batch records (about the size of telephone books) full of comprehensive data that include each step taken during manufacturing and a log of the necessary controls, checks, and balances. These documents are a compilation of production records, test data for raw materials, components, and product integrity. Everything is documented in batch records: the vials used, the equipment used, and the product temperature when machines are in operation, among many other items. Batch records are the ultimate proof that the batch was prepared using established and predefined steps.

Batch record violations. Batch records are often one of the first items that FDA inspectors examine for deviations, missing information, the quality of a company’s documentation practices, and other operating weaknesses. Inspectors want to assess whether the company’s records are comprehensive enough to reflect all production facts, how the company’s quality assurance department reviews the records, how deviations are detected and responded to, and whether there is any missing data in such documents. FDA frequently cites companies that fail to properly analyze their batch record data, that keep inadequate data, that fail to describe deviations in detail, or that provide insufficient responses to deviations. If batches are OOS, companies must understand why and demonstrate that they can correct the problem and prevent recurrence. Such documents can be long and the analysis process tedious, but the process can result in cost savings if the company can identify ways to solve ongoing problems.

Batch records as preventive measures. Batch records can clear a company’s name and disprove suspicions of wrongdoing. In 1982, McNeil Consumer Products, a division of Johnson & Johnson ( and the maker of Tylenol, was faced with product alteration in which Tylenol was laced with cyanide, causing several U.S. deaths. McNeil's batch records helped the company defend its procedures and supported the theory that the problem was not a production deviation but postproduction tampering. Therefore, a company should pay close attention to the contents of its batch records, how those records are filled out during operation, and how the documents are reviewed.

Deviations and Corrections Another frequent focus during inspections is a company’s deviation management and its corrective actions. Deviations can occur during manufacturing, validating, laboratory testing, or program monitoring. Deviation management is a program under which OOS results are reviewed, analyzed, trended, and corrected. Typical questions that an experienced inspector has in mind when inspecting a company’s deviation management and corrective actions are listed in the "Inspecting Deviations" sidebar.

Deviations can take place when manufacturing equipment breaks down or when operators make errors. In these circumstances, it is important to analyze trends in the deviations and to determine the reason for the failures. If there is a trend, what is causing it? Is it user error or improper equipment use? If the equipment is being used improperly, was there an SOP on the machine, and was the SOP being followed? Deviations are red flags that can portend even bigger problems.

Inspecting Deviations
Training A review of the most recent citations issued to companies by FDA shows that many of the issues they cite relate to human error (4). The key to overcoming human error problems is proper and frequent training.

Inspectors examine training records when they reach the conclusion that improper use of the machinery or human errors are the cause of a cited issue. The inspector in these cases will naturally ask if proper training was conducted. Therefore, you need to ask the questions first.

When evaluating your company's training program, be sure to document your responses to training questions. Does a formal program mandate training? Does the training program specify who needs to be trained and on what equipment or processes? Are training materials presented properly by a qualified trainer? Do the training records indicate who was trained and on what equipment or process? Are the records available for inspection? Was training effective in preventing further deviations?

Inspectors can choose to determine the effectiveness of a company's training for themselves. For example, they may observe the gowning procedures for entering classified areas when the cause of a contamination problem was determined to be improper gowning practices. To be proactive and prevent the need for this type of inspection, companies should set up comprehensive training programs that clearly define who needs training, what type of training they need, and how frequently additional or refresher training will be required. Training programs attended should be documented and attached to each employee's record.

Receiving and Inspection Most companies have standard procedures in place for accepting raw materials and consumable commodities. Receivables include not only active ingredients and excipients but also items such as glassware, clean gowns, coveralls, and chemicals or components that are used to manufacture drugs and medical devices.

SOP Failures
A receiving and inspection program needs to define the expectations about each commodity or ingredient being received. The SOPs on the program should state those steps that need to be taken when ingredients or components are received to ensure that the material received meets expected quality attributes. The SOPs may include a review of vendor certificates of analysis and of test results, or they may require internal sampling and testing approved by the quality assurance and quality control (QA/QC) functions within the company. When a company conducts sample tests, it must document the results properly. Companies concerned about quality standards often consider third-party organizations that can conduct tests and confirm the required attributes of the raw materials. If this route is chosen, the outside testing laboratory should be audited and qualified.

Change Control Throughout the manufacturing operation and within all production processes, change is inevitable. New process steps, changes in equipment, and improvements or corrected inadequacies all cause change within a company's operations.

A formal program must be in place to handle changes. Inspectors often focus on this facet of production during an inspection. Inspectors reviewing a company's change control programs will ask if a formal change control program is in place, who administers the program, and which department has ultimate authority over change control. They will ask how the effects of a change are assessed, what steps are taken to minimize or prevent additional impacts, how decisions are made, the thought processes behind change, and who approves them. And, as in all other production processes reviewed, an inspector will want to know how the entire change event, the actions taken in response to the change, and the decisions made regarding the change have been documented.

Documentation Practices People in the biopharmaceutical industry often joke that, "In God we trust, everything else must be documented." That phrase speaks for itself — and for the mountains of documents that regulatory compliance requires.

FDA inspectors insist on reviewing documentation processes. Documents are the only proof that companies have with which to defend their practices and operating procedures. Therefore no amount of effort put into preparing proper documents is in vain. Long before an inspection, review your company's documents . . . and then review them again. Find and fill document gaps, obtain approval signatures, be clear — and, most of all, be factual in your documentation. Always remember, "If you don’t have the proper documentation for an action or item, you don’t have that item, or no action was taken."

To Prepare . . . Perchance to Succeed To biopharmaceutical, pharmaceutical, medical device, outsourcing, or other health care–related companies, an "inspection" translates to an "FDA inspection." But inspections come from other sources as well, from your customers as due diligence audits, from European and other national inspecting agencies, and from potential merger, acquisition, and investing partners.

Preparation for an inspection is critical. Responsible individuals within the company must ask all the questions listed in this article to determine how the company’s operations are functioning. Responsibility must be assigned to those who can ensure success. Rules and regulations can be cumbersome and time consuming, but they serve specific purposes. Proactive managers are those who understand the logic behind the regulations before they attempt to implement them.

References (1) "Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs," Code of Federal Regulations, Food and Drugs, Title 21, Part 210 (U.S. Government Printing Office, Washington DC), revised 1 April 2001.

(2) "Current Good Manufacturing Practice for Finished Pharmaceuticals," Code of Federal Regulations, Food and Drugs, Title 21, Part 211 (U.S. Government Printing Office, Washington DC), revised 1 April 2001.

(3) "Biological Products," Code of Federal Regulations, Food and Drugs, Title 21, Part 600 (U.S. Government Printing Office, Washington DC), revised 1 April 2001.

(4) FDA Warning Letters. Available at (accessed May 2002). BPI

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