◆  Data Integrity and Compliance With Drug CGMP Questions and Answers Guidance for Industry (13-Dec-18 FDA)

The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Data Integrity and Compliance With Drug CGMP: Questions and Answers.” The purpose of the guidance is to clarify the role of data integrity in current good manufacturing practice (CGMP) for drugs. (Unless otherwise noted, the term CGMP refers to CGMPs for drugs, including biologics.) The guidance has been developed in response to an increase in findings of data integrity lapses in recent inspections. FDA expects that all data be reliable and accurate. CGMP regulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues. Firms should implement meaningful and effective strategies to manage their data integrity risks based on their process understanding and knowledge management of technologies and business models.


◆  British Authority MHRA provides Interpretation on Cleaning Validation (13-Dec-18 ECA)

With the introduction of the Permitted Daily Exposure (PDE) values in conjunction with questions on cross contamination and on cleaning validation, the EMA began a new chapter a few years ago. This is a complex issue and it caused uncertainty within the industry. Insofar, the EMA brought a subsequent Q&A document. This is being interpreted by the British Regulatory Authority MHRA with regard to inspection results.

In the development phase of EMA's Q&A document there were different statements, whether Health Based Exposure Limits (HBEL) are binding or not. Some argued with the old 1/1000 dose values. Now, the MHRA has clarified that at present companies have to take charge of respective HBEL values such as PDEs. Referring to Chapter 7 of the EU GMP Guide, the topic "Outsourcing" is also addressed. For the MHRA, simply "do as further as until now" on a risk analysis basis is not acceptable. They miss here the scientific view within the risk analysis. The fundamental requirements of a GMP inspector related to the topics to consider in a risk analysis are listed in the document.

Cleaning Validation and Cross Contamination
Regarding cleaning validation, MHRA's GMP inspectors criticise the missing scientific approach. Often, not all the parts with product contact and decisive cleaning processes (such as manual cleaning) are not integrated in the cleaning validation. The document also provides support with regard to the acceptance of visibly clean criteria in the routine production. There are 11 elements very useful listed in the document to be considered within the scope of cleaning validation.

Conclusion: MHRA's Q&A document entitled "Cross-contamination control and Health Based Exposure Limits (HBEL)" provides practical support with regard to the topic risk analysis in the cleaning and cleaning validation. Hence, it is very worth reading.

For more information please see the MHRA Inspectorate Blog mit dem Titel "Cross-contamination control and Health Based Exposure Limits (HBEL) Q&As".


◆  New ISO Standard for Tamper-Evident Packaging (16-Jan-19 ECA)

On 30 November 2018, the International Organization for Standardization (ISO) published the new ISO standard 21976:2018 entitled "Packaging - Tamper verification features for medicinal product packaging". This standard deals with possible types of tamper-evident seals to ensure the integrity of pharmaceutical packaging. As a basis for the ISO 21976:2018 standard, the DIN working group "Characteristics for checking manipulations on pharmaceutical packaging" proposed the European standard 16679:2014 "Tamper verification features for medicinal product packaging".

Pharmaceutical companies that have prescription drugs in their portfolio must provide these with two security features as of 9 February 2019 in accordance with the Anti-Counterfeiting Directive 2011/62/EU. There are exceptions to this obligation, but for most prescription-only medicines it applies that, from this date at the latest, the (secondary) medicinal product packaging must not only have an individual identification feature but also tamper protection (tamper-evident closure), the so-called "Anti Tampering Device". The delegated EU Regulation 2016/161 provides details on the individual identifier, but not on the technical specifics regarding the device against tampering.

The Question and Answer paper of the EU Commission recommends (in its current version 12 under 1.14.) the CEN standard EN 16679:2014 "Tamper verification features for medicinal product packaging". This standard specifies requirements for tamper evidence for medicinal product packaging and provides guidance on the application, use and verification of the tamper-evident closure. There is a wide range of choices for manufacturers. The ISO standard largely follows the European standard. Manufacturers are therefore not required to make any changes to packaging materials that have already been converted to prepare for the anti-counterfeiting directive.

The ISO Standard 21976:2018 Packaging - Tamper verification features for medicinal product packaging is available for purchase from the International Organization for Standardization.