2013 to 2015 Data Integrity Issues related to Computer Systems

Here is a great resource to gain an understanding of FDA’s perspective on data integrity issues relating to the use of computer systems.  FDA 21CFR Part 11 and the European Union’s focus on data integrity are resulting in an increase in the number of observations during an inspection.

Read more about cases of data integrity issues here. (updated September 2015)

Information compiled by Orlando López, Data Integrity SME.


FDA Issues Adverse Event Reporting Guidelines for Outsourced Facilities

FDA finally bears down on outsourced compounding facilities in 2015, as a result of having found dozens of potentially dangerous safety problems at 30 specialized pharmacies, in 2013, months after tainted steroid shots made by a Massachusetts pharmacy triggered the worst drug disaster in decades.

In 2012, FDA had found filthy conditions at the New England Compounding Center (NECC), the Massachusetts pharmacy at the heart of the fungal meningitis outbreak that killed 53 people and sickened 680 others. These “priority inspections” were focused on firms that produce high-risk sterile products, a key segment of the multi-billion-dollar industry that has fallen between the regulatory cracks. Read more about the corporate criminal acts committed by NECC.

Outsourcing Facility Registration and Reporting

The new law allows an entity that compounds sterile drugs to register as an outsourcing facility. Once registered, an outsourcing facility must meet certain conditions in order to be exempt from the FDCA’s approval requirements and the requirement to label products with adequate directions for use. Under the new law, the drugs must be compounded in compliance with CGMP by or under the direct supervision of a licensed pharmacist in a registered facility (section 503B(a)). The outsourcing facility must also report specific information about the products that it compounds, including a list of all of the products it compounded during the previous six months, and information about the compounded products, such as the source of the ingredients used to compound (section 503B(3)). In addition, the outsourcing facility must meet other conditions described in the new law, including reporting adverse events and labeling its compounded products with certain information (section 503B(b)(5) and section 503B(a)(10)).

Under the new law, an outsourcing facility will not be considered registered until it has paid the applicable annual registration fee (see section 744K(g)(3)(A)). An outsourcing facility may register without paying a fee until September 30, 2014, however, because fees are not required until October 1, 2014. In addition, the new law requires that outsourcing facilities register and report their products to FDA electronically unless the Secretary grants a request for a waiver of such requirement because use of electronic means is not reasonable for the person requesting the waiver (section 503B(b)). FDA has issued draft guidances on registering and reporting for those entities that intend to register as outsourcing facilities.

Download the guidance for adverse event reporting here.

ICH E6 (R2) GCP Guidelines Issued for Review

The ICH GCP guidelines have been modified to address the following:

  • electronic records and controls (reflects 21CFR Part 11 requirements)
  • validation of computer systems used for GCP
  • risk management approach on behalf of the sponsor and the CRO to evaluate, identify, control, mitigate, and communicate the major risks
  • oversight responsibilities of the sponsor
  • integrity of the data (the new FDA hot button)
  • risk based monitoring

Download the guidelines here.

Guidance for Industry: Dissolution Testing and Specification Criteria

FDA has issued the guidance, Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs (August 2015). This will supersede the guidance issued in August 1997 for BCS Class 1 and 3 drug substances in immediate-release drug products that meet the criteria of the guideline.  For Class 2 and 4 drug substances, continue to refer to the 1997 guidance document. Class 2 is Low solubility-High Permeability Drugs, while Class 4 is Low solubility-Low Permeability Drugs. The guideline applies to solid oral dosage forms and not chewable or orally disintegrating tablets.

Download the guidance here.


MHRA GMP Data Integrity Definitions and Guidance for Industry – March 2015

The MHRA published a guideline for industry for the integrity of GMP data. This guideline applies to the pharma and medical device industries.  This is a great guideline to use to update your SOP on Recording CGMP data.  If you don’t have such an SOP, now is the time to develop one.  Both the FDA and EMA will be looking at your data integrity expectations and practices.

For example, you need to train personnel on the expectation that data (Information derived or obtained from raw data (e.g., a reported analytical result) will comply with the following (ALCOA):

Attributable: The identity of the person who made the entry must be unique and obvious and the date when the entry was made must be included.

Legible: Readable and able to identify the person who generated the record.

Contemporaneous: The information must be documented in the correct time frame along with the flow of events.  Chronology must be apparent. Any delays must be explained.

Original: The original data must preserve data accuracy, completeness, contents and meaning, including the meta data.  If not original, then it should be an exact copy, signed and dated by the person who made the entry.

Accurate: Accurate, consistent and real representation of facts

Some people don’t know what raw data is: Original records and documentation, retained in the format in which they were originally generated (i.e. paper or electronic), or as a ‘true copy. Raw data must be contemporaneously and accurately recorded by permanent means. In the case of basic electronic equipment which does not store electronic data, or provides only a printed data output (e.g., balance or pH meter), the printout constitutes the raw data.

While we are on the subject of data integrity, you should also have an SOP on Scientific Integrity.  It should be a company policy whereby Senior Management communicates their position on scientific conduct and ethics.  This is a key SOP that a lot of companies don’t have.

We have seen scientific integrity issues at NIH,  in Japan  and many other sites and countries.  These occurrences are what has triggered both FDA and the EMA to focus more on data integrity during routine and PAI inspections.

Download the guidance here.

Vision for the 21st Century: FDA publishes Quality Metrics Guidance

Request for Quality Metrics: Guidance for Industry (July 2015) is a significant draft guidance you need to address in terms of the Annual Product Reviews (APRs) that are conducted annually, and what should be included either within the APR or as a separate analysis.

The guidance applies to both APIs and FDFs (finished dosage forms). As a proactive measure, we are suggesting that you initiate this system by the time you are in Phase 3 clinical development, if not earlier, depending if you are on a fast track development cycle or expedited review. This will facilitate compliance with management and cross functional departments on the expectation of what is important to analyze during development as you enter the life cycle for the product, even though it is in development.

Our experience is such that companies lose a lot of valuable information during development, because it is not analyzed adequately and used to make incremental improvements during clinical manufacturing.

FDA notes that the following baseline quality metrics will be requested as part of their risk based analysis that could either reduce or increase the inspection frequency at a site.  FDA hopes to reduce inspection frequencies for companies that have robust quality metrics.

  • The number of lots attempted of the product. (See 21 CFR 211.165, 211.188)
  • The number of specification-related rejected lots of the product, rejected during or after manufacturing. (See 21 CFR 211.192, 165(f))
  • The number of attempted lots pending disposition for more than 30 days. (See 21 CFR 211.188. Under current good manufacturing practice, deviation investigations and final disposition decisions must be completed in a timely manner. Note that the request for lots pending disposition more than 30 days was selected as a measurement tool and not intended to clarify the timely manner in which disposition should be completed. Further, a lot may be subdivided or grouped after the first attempted lot is initiated. Each subsequent subdivision or grouping is considered a separate lot. These data will be used to verify data validity supporting the lot acceptance rate metric).
  • The number of out-of-specification (OOS) results for the product, including stability testing. (See 21 CFR 211.160(a). For the purpose of this guidance, this includes: (1) finished product and stability test results only and, (2) all finished product and stability test results that initially appear as OOS, even if invalidated by a subsequent laboratory investigation).
  • The number of lot release and stability tests conducted for the product. (See 21 CFR 211.165, 211.194(a), and 610.1. If a lot release or stability test is conducted multiple times for a lot, each test should be counted.)
  • The number of OOS results for lot release and stability tests for the product which are invalidated due to lab error. (See 21 CFR 211.160(a). While this guidance is requesting data specific to lot release and stability tests, FDA recognizes the importance of other types of testing (e.g., in-process testing, environmental testing, raw material and packaging component testing).
  • The number of product quality complaints received for the product. (This quality data is the total number of all product quality complaints, as defined in the Glossary. This does not include multiple counting of the same product quality complaint if the complaint receiver forwards the complaint to individual manufacturers for further investigation).
  • The number of lots attempted which are released for distribution or for the next stage of manufacturing the product. (See 21 CFR 211.150(b)).
  • If the associated annual product reviews (APRs) or product quality reviews (PQRs) were completed within 30 days of annual due date for the product. (See 21 CFR 211.22(d); 211.180(e). The data for APRs and PQRs not completed within 30 days was selected as a measurement tool and not intended to clarify the timely manner in which APRs and PQRs should be completed).
  • The number of APRs or PQRs required for the product.  (See 21 CFR 211.22; 211.180(e).

In the draft guidance document, FDA lists four quality metrics it intends to calculate for each product and establishment, where applicable.  Note that the expectation is to complete APRs within 30 days and not within 3 months as most companies specify in their SOPs.

  • Lot Acceptance Rate = 1 – x (x = the number of specification-related rejected lots in a timeframe divided by the number of lots attempted by the same establishment in the same timeframe).
  • Product Quality Complaint Rate = the number of product quality complaints received for the product divided by the total number of lots of the product released in the same timeframe.
  • Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished product invalidated by the establishment divided by the total number of OOS test results divided by the total number of tests performed by the establishment in the same timeframe.
  • Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number of APRs or PQRs completed within 30 days of annual due date at the establishment divided by the number of products produced at the establishment.

Download a copy of the draft guidance here.

Analytical Procedures and Methods Validation for Drugs and Biologics

FDA has published “Analytical Procedures and Methods Validation for Drugs and Biologics” (July 2015). This is a very significant document as it is replacing the 2000 guidance and it now reflects ICH Q2(R1) guidances.

The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and supplements to these applications. The principles in this guidance also apply to drug substances and drug products covered in Type II drug master files (DMFs).

The guidance also suggests that a risk-based approach concerning revalidation of existing test methods should be employed when the manufacturing process changes during the product’s life cycle. The guidance recommends the outline of what should be included when preparing an analytical method procedure. The guidance clearly states that USP methods should be verified through a written verification protocol.

Download the guidance here.

Annual report of the Good Clinical Practice Inspectors Working Group

The 2014 Annual report of the Good Clinical Practice Inspectors Working Group was adopted by the GCP IWG on 05 March 2015.

Of the 57 GCP inspections carried out by the EU member states, there were a total of 673 deficiencies. Thirty (30) were critical, 290 were major and 353 were minor. Almost 20% of the deficiencies are related to essential documents.

See a full analysis of the results of these inspections and download the final report here.

Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products

In June, 2015, FDA issued a CDER/CBER guidance document on FDA’s current thinking on allowable excess volume and labeled vial fill size for injectable drugs and biologics.  The guidance is only 5 pages long and discusses the need to comply with current USP requirements for excess volume and the need to provide justification through extractable content testing data (USP Chapter <1> under Packaging, Determination of Volume of injection in Containers).  General fill volume should be based on what is considered a usual or maximum dose for the expected use of the drug product.  FDA is requesting that users of the drugs or biologics not be required to use more than 1 vial to administer a typical single dose of drug product.  For multi-dose vials, no more than 30 mL of drug product should be filled in the vial.

If excess volume is added to the drug product, it should be described in the CTD section 3.2.P.1 and should be justified with the appropriate studies.

Overfill is not the same as overage, the latter being an amount of drug substance in excess of the label claim.  This is further discussed in the ICH Guidance for Industry, Q8(R2), Pharmaceutical Development.

Download the guidance here.