To Qualify or Not to Qualify your Excel Spreadsheets? There is no Question!

We have been asked many times during audits about the use of Excel spreadsheets. We have seen numerous examples of uncontrolled excel spreadsheets being used for QC testing.

This example of a warning letter from an August 2011 inspection of an OTC firm, Compañía Internacional de Comercio, S.A. de C.V., in Mexico that highlights the importance of qualifying your Excel spreadsheet.

Excel spreadsheets, when used for calculations, must be qualified. It is difficult to validate the spreadsheets, but companies must manage the spreadsheets in the same manner that they would a software program and controlled documentation.

Here are some tips to consider when working with Excel spreadsheets that calculate formulas and are used to determine the status of the material/product against the specification.

  • Put the spreadsheet on the network server in a limited access folder with read-only ability.
  • Test the spreadsheet prior to protocol execution (pre-qualification).
  • Ensure the precision of final calculations meet the requirements for SOP on rounding and significant figures.
  • Ensure that the precision of the final calculations meet the specification requirements
  • Document training for spreadsheet users.
  • Maintain limited access for use. Establish and control password access.
  • Review security and control issues related to spreadsheet use. Train personnel to access spreadsheet directly from network drive.
  • Maintain version control.
  • Control and save electronic data files.
  • Ensure back-up and recovery.

When you are ready to qualify the spreadsheet, develop a formal Qualification Protocol. Include items like the following:

  • Spreadsheet Name: State the name of the spreadsheet. Obtain a spreadsheet number from QA
  • Purpose: Describe the use of the spreadsheet.
  • Spreadsheet Owner: Identify the owner of the spreadsheet
  • Responsibilities: Include the spreadsheet owner, the user and QA as the parties responsible for the spreadsheet including version control.
  • Software Functions: Define the functions of the software: Identify manually input cells; identify software formulas; specify the expected outputs
  • Test Plan: Define the test plan. Test at least three sets of test values for each formula:
  • Describe the functions to be tested.
  • Ensure that the test plan adequately tests security of the spreadsheet.
  • Specify each step to be performed.
  • Specify the equipment and methods to be used.
  • Deviations, Exceptional Conditions, and Corrective Actions: Include form to document deviations, exceptional conditions and corrective actions observed during spreadsheet qualification.
  • Acceptance Criteria: Include a list of the acceptance criteria.
  • Approval: Identify who will review and approve the Protocol
  • Spreadsheet Owner
  • Department Director
  • Quality Assurance

Prepare and approve a formal report. Include a copy of the spreadsheet with the executed data information and a copy of the hand calculations.

MWA can assist you with your software validation needs. Contact us for more information.

Supply Chain Security: Considerations for Third Party Logistics

Rx-360, an international pharmaceutical supply chain consortium, is a great resource for the latest in controls and considerations for Logistics Service Providers (LSPs). LSPs provide clients with warehousing, distribution, and logistics services. As we know, there is much more focus on the integrity of the supply chain, for which LSPs play an integral part.

In June, 2012, Rx-360 published a draft template outlining the Requirements for Third Party Logistics Providers. This template can serve as the basis for a quality agreement that you establish with your LSPs. The considerations identified within the template will help ensure the integrity of your material while under the control of the LSP.

Rx-360 has also developed an excellent audit tool for consideration when auditing Third Party Logistic Service Providers. It addresses physical security, access control, records and logs, procedural security, personnel security, cargo security, control of goods in the facility, returned and rejected product storage, security, reporting and notification, and protection of information.

Read more here.

EMA: New Notes for Guidance on Process Validation

In March 2012, EMA replaced the Notes for Guidance on Process Validation (CPMP/QWP/848/96). This guidance, similar to the recently issued FDA guideline, incorporates many of the concepts noted in the ICH guidelines Q8, Q9 and Q10. The guideline is somewhat harmonized with the current FDA
guidance on Process Validation. The guidance document does not deal with legacy products, but rather addresses new products and the approach to ensure appropriate process validation is performed.

Process validation is addressed by using four different approaches: Traditional process validation, Continuous process verification (CPV), Hybrid approach and Continued Process Verification during the Lifecycle. Each approach is described within the guidelines. There are also definitions that are repeated in this guideline from ICH Q8 and Q9.

Read the new guidance here.

ICH Guideline on Development and Manufacture of Chemical Entities and Biotechnological/Biological Drug Substances

ICH has finalized Q11 Guideline on development and manufacture of chemical entities and biotechnological/biological drug substances, effective May 2012. The guideline describes approaches to developing and understanding the manufacturing process of the drug substance, and provides guidance on what information should be provided in Module 3 of the Common Technical Document (CTD) sections 3.2.S.2.2 – 3.2.S.2.6. There are differences between the draft and the final document in the areas of design space and critical quality attributes.

Read the guideline here.

FDA finalizes the regulatory change to expand the scope of clinical investigator disqualification

FDA finalized the regulatory change to expand the scope of clinical investigator disqualification effective May 30, 2012. Under the new ruling, when the Commissioner determines that an investigator is ineligible to receive one kind of test article (drugs, devices or new animal drugs), the investigator also becomes ineligible to conduct any clinical investigation that supports an application for research or marketing permit for other kinds of products regulated by FDA. This stricter enforcement was recommended by the GAO, which concluded that it is “critical for FDA to take action-and to have the authority to take action to prevent clinical investigators who engaged in serious misconduct from doing so again, whether in research that involves drugs, biologics, or devices.”

Read the new regulations here.

Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET) Drugs

FDA released the following Guidance Document, effective April 2012: Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET) Drugs.

This guidance is intended to help manufacturers of positron emission tomography (PET) drugs meet the requirements for the Agency’s current good manufacturing practice (CGMP) regulations for PET drugs (21 CFR part 212). Most PET drugs are designed for parenteral administration and are produced by aseptic processing.

Additionally, until June 12, 2012, FDA does not intend to take enforcement action against a PET facility currently producing PET drugs for clinical use for a failure to submit a new drug application by December 12, 2011, provided that the facility complies with all other FDA requirements, including current good manufacturing practices (CGMPs). FDA will not exercise enforcement discretion after June 12, 2012. Therefore, if a facility wishes to continue to produce PET drugs for clinical use after June 12, 2012, they must have submitted a new drug application (NDA) or an abbreviated new drug application (ANDA) by that date, or be producing the drugs under an investigational new drug application (IND).

Read the guidance here.

“Risk takes a new dimension” : PIC/S Aide-Memoire

Effective 2 April 2012, PIC/S (Pharmaceutical Inspection Cooperation Scheme) published an Aide-Memoire for GMP inspectors on inspections of quality risk management (QRM) systems. The document defines what companies can expect GMP inspectors to be looking for regarding risk management. The document is based on ICH Q9: Risk Management. There are 5 sub-chapters that address:

  1. Overall Systems: does the company use a Quality Risk Management approach, is Senior Management involved in the process, and if there are issues, does Senior Management take action?
  2. Expectations on how QRM should be implemented: Is the process scientific based and does it take prior experience into consideration, and have staff been trained on risk management tools?
  3. Specific Areas and Activities where Implementation of QRM might be expected: QRM would be expected in many areas of the quality system, like, deviations, OOS, CAPA, complaints, change control, sampling and testing, supplier qualification, validation, audit program, etc.
  4. Review of Residual Risk: This addresses assessing the effectiveness of the risk decisions and plans if additional information is forthcoming. This section references ICH Q10 as the model for management review.
  5. Review and improvement of QRM activities: does the company periodically review the QRM system as part of management review and to promote continual improvement of the system?

Read the documentation here.

Changes to CGMPs for Human and Veterinary Drug Products

The following is excerpted from the attachment and summarizes the changes to the CGMPs. This is a significant change to the GMPs and reflects FDA’s confidence in automated technology as well as their risk management approach to patient safety.

Food and Drug Administration (FDA) is amending the packaging and labeling control provisions of the current good manufacturing practice (CGMP) regulations for human and veterinary drug products by limiting the application of special control procedures for the use of cut labeling to immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons. FDA is also permitting the use of any automated technique, including differentiation by labeling size and shape that physically prevents incorrect labeling from being processed by labeling and packaging equipment when cut labeling is used. This action is intended to protect consumers from labeling errors more likely to cause adverse health consequences, while eliminating the regulatory burden of applying the rule to labeling unlikely to reach or adversely affect consumers. This action is also intended to permit manufacturers to use a broader range of error prevention and labeling control techniques than permitted by current CGMPs.

Read the full text here.

New & Revised Draft Guidances from CDER coming in 2012

On March 6, 2012, FDA’s Center for Drug Evaluation and Research (CDER) published a Guidance Agenda listing the new and revised draft guidance documents CDER plans to publish during 2012. There are over 50 guidances planned. We will have a busy year reading, understanding and complying with these new and revised guidances. Welcome to the 21st century! Let MWA know how we can assist you with your compliance needs.

Read the complete guidance agenda here.