Stability Testing related News Vol.1

◆  New Details on the Revision of USP Chapter 1 (13-Apr-16 ECA)


USP’s Chapter <1> “Injections and Implanted Drug Products (Parenterals)-Product Quality Tests’ has been revised again. New information is now available.


The USP published these details on 25 March. The revised version now contains a table of contents for a better overview whereas the Product Performance Test at the end of the Chapter has been deleted. All details about the new version of USP’s Chapter <1> can be found on the USP website.



◆  New FDA Draft Guidance ‘Data Integrity and Compliance with cGMP’ published (27-Apr-16 ECA)


In recent years, the topic “data integrity” has become a priority for European and American inspectors. At the beginning of 2015, the British authority MHRA published a first paper on that topic. Also in 2015, the World Health Organisation WHO issued another significant draft document on data integrity. Recently, the US American FDA has released the draft of a Guidance for Industry entitled “Data Integrity and Compliance with cGMP”. Although the FDA describes the Guidance as a non-binding recommendation, one may assume that the document presents the current thinking of the FDA regarding the topic.


The FDA criticises the fact that more and more cGMP deficiencies with regard to data integrity have been observed during inspections. Those deficiencies have led to a number of follow-up measures like Warning Letters or import alerts.


For the FDA, the integrity of data is one of the main quality issues. In the Guidance, the corresponding reference points in parts 21 CFR 211 and 21 CFR 212 are listed in detail as well as the principles for electronic records laid down in 21 CFR Part 11.


  • 211.68 (requiring that “backup data are exact and complete,” and “secure from 48 alteration, inadvertent erasures, or loss”)
  • 212.110(b) (requiring that data be “stored to prevent deterioration or loss”)
  • § 211.100 and 211.160 (requiring that certain activities be “documented at the time 51 of performance” and that laboratory controls be “scientifically sound”)
  • 211.180 (requiring that records be retained as “original records,” “true copies,” or 53 other “accurate reproductions of the original records”)
  • § 211.188, 211.194, and 212.60(g) (requiring “complete information,” “complete 55 data derived from all tests,” “complete record of all data,” and “complete records of 56 all tests performed”).


The most important topics for the FDA are presented in the quite rare but not unusual form of questions and answers. The document contains 18 questions with their respective answers.


  1. Clarification of terms

– What is “data integrity”?

– What is “metadata”?

– What is an “audit trail”?

– How does FDA use the terms “static” and “dynamic” as they relate to record formats?

– How does FDA use the term “backup” in § 211.68(b)?

– What are the “systems” in “computer or related systems” in § 211.68?

  1. When is it permissible to exclude CGMP data from decision making?
  2. Does each workflow on our computer system need to be validated?
  3. How should access to CGMP computer systems be restricted?
  4. Why is FDA concerned with the use of shared login accounts for computer systems?
  5. How should blank forms be controlled?
  6. How often should audit trails be reviewed?
  7. Who should review audit trails?
  8. Can electronic copies be used as accurate reproductions of paper or electronic records?
  9. Is it acceptable to retain paper printouts or static records instead of original electronic records from stand-alone computerized laboratory instruments, such as an FT-IR instrument?
  10. Can electronic signatures be used instead of handwritten signatures for master production and control records?
  11. When does electronic data become a CGMP record?
  12. Why has the FDA cited use of actual samples during “system suitability” or test, prep, or equilibration runs in warning letters?
  13. Is it acceptable to only save the final results from reprocessed laboratory chromatography?
  14. Can an internal tip regarding a quality issue, such as potential data falsification, be handled informally outside of the documented CGMP quality system?
  15. Should personnel be trained in detecting data integrity issues as part of a routine CGMP training program?
  16. Is the FDA investigator allowed to look at my electronic records?
  17. How does FDA recommend data integrity problems identified during inspections, in warning letters, or in other regulatory actions be addressed?

Source: FDA Draft Guidance for Industry “Data Integrity and Compliance with cGMP”



◆ USP publishes draft of a new general chapter <661.3> for plastic components used in manufacturing (11-May-16 ECA)


In the Pharmacopoeial Forum (PF)  42(3) (May-June 2016) the USP General Chapters – Packaging and Distribution Expert Committee proposes a new chapter to address the qualification of plastic components used in the manufacture of APIs (pharmaceutical and biopharmaceutical) and drug products (DPs). The proposed Title of the new chapter <661.3> is Plastic Components and Systems Used in Pharmaceutical Manufacturing. The draft is open for comment until July 31, 2016.


The chapter is part of a suite of chapters, including Plastic Packaging Systems and Their Materials of Construction <661>, Plastic Materials of Construction <661.1>, Plastic Packaging Systems for Pharmaceutical Use <661.2>, and Evaluation of Plastic Packaging and Manufacturing Systems and Their Materials of construction with Respect to Their User Safety Impact <1661>. In addition a section has been added to general chapter <1661> to support the use and understanding of the new general chapter <661.3>. The revision of general chapter <1661> (including change of title) also appears in the PF issue 42(3).


The chapter <661.3> addresses the qualification of plastic components used in pharmaceutical manufacturing and is applicable solely to those processes that involve liquid process streams and process intermediates due to the expected increased degree of interaction with liquids. Plastic manufacturing systems for pharmaceutical use include – for example – bags, cassettes, chromatographic columns, connectors, filling needles, filters, sensors, tanks, tubing, and valves. Elastomeric parts such as diaphragms, gaskets, and O-rings are not in the scope of this chapter. A flow diagram that shows a typical bioprocess DP production suite is shown in general chapter <1661>, Figure 2.


The manufacturer of APIs and DPs is responsible for ensuring that the plastic components and systems used are suited for the intended purpose. It is likely that raw materials, intermediates, process streams, APIs, and DPs will get in contact with one or more plastic component(s) of the manufacturing suite during the manufacturing process, resulting in process-related impurities (PrIs). PrIs have the potential to alter a quality attribute of the DP, if the PrIs persist through the manufacturing process.


Plastic manufacturing components and systems are chemically suited for their intended use with respect to safety if:

  • they are constructed from well-characterized materials that have been intentionally chosen for use as established by the test methods included in general chapter <661.1>;
  • The general physicochemical properties of the components have been established;
  • The biocompatibility (biological reactivity) has been appropriately established;
  • They have been established as safe by means of the appropriate chemical testing, such as extractables or leachables profiling and toxicological assessment of the test data (“chemical safety assessment”).


The chapter provides guidance on the appropriate application of biological reactivity tests (reference to general chapters <87>, <88>) and physicochemical tests (reference to Food Additive regulations and general chapter <661.1>, where applicable) for manufacturing components and systems. A two-stage approach consisting of an Initial Assessment followed by a Risk assessment leads to the required level of component characterization. The Initial Assessment examines the factors present for demonstration of equivalence with a comparator component or system by looking at the following parameters:

  • purpose and composition of component or system;
  • composition of DP(s);
  • processing conditions;
  • product dosage form.


The demonstration of equivalence would allow acceptance of the component (or system) without any further characterization. If equivalence cannot be established between the component (or system) under consideration and the comparator, then a Risk Assessment should be conducted. The risk assessment matrix is provided in detail in general chapter <1661>. The outcome of this assessment results in three risk levels: low (A), moderate (B), and high (C). These levels are linked according to the risk of the individual dosage form (e.g. solid oral and liquid oral, others than solid oral and liquid oral) to test requirements as shown in the draft chapter <661.3>. All three risk levels require identification of the component or system as specified in general chapter <661.1>. Identity is only required for those components or systems that consist of single materials of construction (individual polymers only). Biological reactivity testing according to USP general chapter <87> (In Vitro) is required for all levels plus testing according to Class VI in <88> (In Vivo) for Level B and C.  Level A and B require that the component or system be tested as specified in general chapter <661.1> for physicochemical characteristics and extractable metals characteristics. Level C components (or systems) must be characterized more rigorously than level A and B components in view of the extractables profile.

Additives: For level A components reference to 21 CFR Indirect Food Additive regulations is sufficient, for level B components additives are determined by testing, and for level C components extraction studies have to be performed.


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