GMP UPDATE - WHAT'S NEW IN EUROPE?
The year 2015 was an eventful year, just as the years before. Again there were new developments in the GMP environment as well as announcements of changes that preoccupy the pharmaceutical industry. 2016 won't be less exciting, also because now many of the new requirements must be implemented.
What are the reasons for all these new developments? One reason still is the Directive 2011/62/EU the so-called Directive on falsified medicinal products (FMD) and the resulting changes and adaptations in other areas. Other reasons are problems and challenges that have occurred in the supply chain of medicinal products.
The deadline approaches: As of February 2019 safety features must be affixed to the packaging of all medicinal products subject to prescription but also to the packaging of critical medicinal products not subject to prescription in order to permit identification and unambiguous tracing. The outer packaging, or if it doesn't exist, the primary packaging of each medicinal product must present safety features that allow for the verification of the authenticity of the medicinal product and for the identification of individual packs. Furthermore, a device is required allowing verification of whether the outer packaging has been tampered with. When certifying a batch the Qualified Person shall be obliged to ensure that the safety features have been affixed to the packaging in the correct way.
Implementation will be carried out by means of a 2D matrix code. Concerning this a draft of the Commission Delegated Regulation as well as drafts of the Annexes I-IV were published in August 2015. Final date for comments was 11 October 2015. This document containing 34 pages sets out the technical specifications of the planned safety features (a 2D matrix code - harmonised in Europe) but not the specifications of the planned device to safeguard the authenticity. Moreover, the holistic end-to-end system is described with risk-based verifications at wholesaler level and the corresponding data repositories:
Recommendation
Berlin, Germany4/5 December 2024
Root Cause Analysis
GDP: Good Distribution Practice for Active Ingredients.
The Guidelines on Good Distribution Practice for Active Substances for Medicinal Products for Human Use which were published on 19 March 2015 have been in force since 21 September 2015. This is irrespective of whether they are produced by the distributor himself, by someone else or whether they are imported. Distribution comprises all activities such as procuring, importing, holding and transporting, selling, supplying or exporting with the exception of brokering. The right of authorities to inspect distributors follows from this. Repackaging or relabeling are manufacturing activities and are regulated by GMP.
Distributors of active substances should implement a quality system setting out responsibilities, processes and risk management principles. As required by the GDP Guidelines they must have enough competent personnel, for example, and they must designate a person with defined authority and responsibility ("designated person") at each location where distribution activities are performed.
The main changes in the new EU Guidelines to Good Manufacturing Practice chapter 3 "Premises and Equipment" concern the sections on measures to prevent cross-contamination. The changes are closely associated with the revision of chapter 5 (Production) and with the new EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/CVMP/SWP/169430/2012). The old text, especially part 3.6 caused problems of interpretation, for example with tablets containing anabolic steroids or certain hormones and with injectable drug products containing growth hormones and erythropoietin. The new text seeks for a risk-based assessment on the basis of toxicological data. This means that dedicated facilities are only required if the identified risks cannot be controlled using adequate technical or organisational measures (these technical or organisational measures are described in chapter 5), if limits are impossible to be defined (e.g. allergenic potential such as in the case of beta-lactam) or if the limits are so low that they cannot be determined by a valid analytical method.
This is supported by EMAs Toxicological Guideline, mentioned above. It has been valid since 1 June 2015 and describes a risk assessment based on a toxicological evaluation of the products manufactured in the shared facility/ production area. This can be based on all available toxicological or clinical data, therefore also on data from literature. In future, it will replace for instance the 1/1000 dosage or the 10 ppm criterion used so far in cleaning validation. Basis is now the so-called permitted daily exposure (PDE) which can, however, only be used for substances with a known pharmacological or toxicological exposure limit. If the limit is not known (so far) - as is the case for instance during development - alternative methods can be chosen. This means that substances with a genotoxic or a sensitising potential are also excluded. In this case the PDE approach cannot be used because, theoretically, any resorption could create a risk.
Even though the Guideline already is in force it will be implemented step by step:
For compounds introduced for the first time - 1 June 2015
For already existing shared manufacturing facilities (human medicines) - 1 December 2015
For already existing shared manufacturing facilities (human and human and veterinary medicines) - 31 May 2015
For already existing shared manufacturing facilities (only veterinary medicines) - 1 June 2016
The new Chapter 5 "Production" of the EU Guidelines to Good Manufacturing Practice has been in operation since 1 March 2015. This chapter contains much more changes - relating to:
- suitable technical measures to prevent cross-contamination; as already mentioned, the description has been enhanced - for instance concerning the use of closed systems (RABS or isolator), a localised extraction of dust, the use of dedicated equipment or dedication of parts including the corresponding tools for repair and maintenance, the use of disposables, appropriate pressure cascades and air-locks, validated CIP processes and separated washing zones;
- organisational measures to prevent cross-contamination; this description was complemented, too - for example for campaign production followed by a specific cleaning process and subsequent cleaning verification, the keeping of specific protective clothing inside high-risk areas, a verification of cleaning of non product contact surfaces and/or monitoring for possible contaminations and specific measures for waste handling, documentation and training;
- the use of quality risk management processes;
- the requirements concerning selection, qualification and trending of starting materials, packaging materials and their suppliers;
- the controlling of the supply chain's traceability;
- the requirements concerning the adoption of (data) from certificates of analysis of the manufacturer or supplier;
- the requirements concerning the notification of authorities in the case of restrictions in production or supply.
Annex 15 of the EU Guidelines to Good Manufacturing Practice "Qualification and Validation" also became effective in its revised version (1 October 2015). It takes over principles from the ICH Guidelines Q8, Q9, Q10 and Q11 with reference to the application of Quality Risk Management (QRM), Process Analytical Technology (PAT), Quality by Design (QbD) and Real-Time Release Testing (RTRT).
The Annex is valid in general for pharmaceutical products with chemical active ingredients. But the principles can also be applied to active pharmaceutical ingredients and to pharmaceutical products with biological active ingredients. It was coordinated with the EMA Guideline "Guideline on process validation for finished products - information and data to be provided in regulatory submissions" (in operation as of 24 August 2014). The corresponding guideline for biotechnology-derived products from April 2014 has just been issued in its final version ("Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission") and will become effective on 1 November 2016.
The new Annex 15 lays down extended requirements on the validation master plan and on the documentation. Any changes to the protocol or failure to meet an acceptance criterion should for instance be documented as a deviation (so far they were only required to be documented and justified). A summary assessment of the validation results is still required. Conditional approval can be given where a risk analysis shows that there is no significant impact on the next activity.
New is a general requirement for user requirement specifications (URS), factory acceptance test and site acceptance test (FAT/SAT).
There were few changes relating to the expectations concerning IQ/OQ/PQ. They can be summarised in justified cases.
The most important changes concern process validation itself (consistent with the EMA Guideline mentioned above). A so-called retrospective validation is obsolete now. Nowadays authorities favour a prospective validation and - in special cases, but never as a routine procedure - a concurrent validation.
Two principal approaches are possible to process validation; the "traditional" one with a minimum of three consecutive validation batches and a continuous process verification with reference to QbD. They can also be mixed (hybrid approach).
An ongoing process verification should be carried out after modifications of processes. It requires a sufficient process understanding. The ongoing process verification should also be carried out if the initial validation was traditional.
The requirements concerning the cleaning validation are described in more detail and go hand in hand with the requirements in Chapter 3 and with the "Toxicological Guideline", for example when calculating the acceptance criteria. Furthermore maximum holding times have to be defined ("maximum dirty holding time", "maximum clean holding time"). A cleaning verification is only acceptable for investigational medicinal products (IMPs) or for products which are only manufactured infrequently and requires a justification based on the principles of risk management. In the case of changes in the processes (incremental changes) these must be taken into account during requalifications (corresponds to revalidation in the former Annex 15). Where manual processes are used, such as for cleaning, the effectiveness of the process should in any case be confirmed at a justified frequency.
The chapter on transport verification in Annex 15 is completely new. The chapter recognises that it is difficult to validate transports. It is recommended to also monitor other critical parameters apart from temperature - such as vibration, humidity etc.
By the way, FDAs "new" Guidance on Process Validation has been valid since January 2011. There is a (satisfyingly) high level of agreement between the FDA Guidance on Process Validation and the revised Annex 15. To improve consistency with the FDA Guidance on Process Validation was one of the reasons for the revision of Annex 15. But there are also differences that companies wishing to serve the US market as well as the European market must be well aware of. One difference for instance concerns the number of validation batches. Annex 15 still refers to the minimum number of three whereas no number is mentioned in the FDA Guidance on Process Validation. A further difference concerns the approaches to process validation: the FDA Guidance makes no difference between traditional approach, continuous process verification and the hybrid approach. Furthermore, the two documents contain different requirements for the use of statistics. There is a stronger emphasis on this topic in the FDA Guidance on Process Validation. There are also differences concerning sampling during the validation life cycle (continued/ongoing process verification). The FDA requires a higher number of samples, at least until sufficient data is collected in order to be able to estimate variability. Annex 15 does not mention this requirement in the ongoing process verification.
The long awaited Annex 16 "Certification by a Qualified Person and Batch Release" was finally published in October 2015. It is pointed out that the principal task of a Qualified Person (QP) is to certify batches for their release. In this context the QP must verify personally that the responsibilities listed in chapter 1.6 are fulfilled. Chapter 1.7 lists many further responsibilities of the QP. But the related activities may be delegated and in doing so the QP can rely on the respective quality management systems. But the QP should make sure continuously that this confidence is justified.
It should be pointed out in this context that the ultimate responsibility for a medicinal product over its lifetime, its safety, quality and efficacy lies with the marketing authorisation holder. The Qualified Person is responsible for the single batches.
During the consultation phase interest groups have expressed concerns relating to the sampling in connection with imported products. Now the new Annex 16 makes clear: "Samples may either be taken after arrival in the EU, or be taken at the manufacturing site in the third country (...) which is documented within the company's quality system. (...) Any samples taken outside the EU should be shipped under equivalent transport conditions as the batch that they represent."
It is the first time that the GMP expectations concerning excipients are described in a guideline. The "Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use" were published in March 2015. Central topic is that the manufacturing authorisation holder (MAH) is required to ensure that the excipients are suitable for use in medicinal products. For this the MAH shall determine on the basis of a formalised risk assessment the appropriate good manufacturing practice expected. This means that Part II of the EU GMP Guidelines was not extended to include excipients. Here, the manufacturer is lucky to have a certain degree of freedom. But this also means that these Guidelines do not represent requirements for the manufacturers of excipients since these are not subject to the pharmaceutical regulations. The manufacturing authorisation holder is responsible. But what provides guidance for the manufacturer of excipients? There are some semi-official guidelines such as USP <1078> GMP Guide for Bulk Pharmaceutical Excipients, IPEC-PQG Excipient GMP or EXCi- PACT™* GMP.
The ICH Q3D Guideline for Elemental Impurities was published at the end of 2014. EMA published the relevant recommendations (EMA Elemental impurities in marketed products - Recommendations for implementation) on 26 February 2015. These recommendations address manufacturers of medicinal products and the national regulatory authorities. The latter should comply with the recommendations when carrying out their activities in order to ensure a consistent approach. This should also reduce the workload for the handling of variations that are assessed according to the same criteria. It will have to be seen in what way the document's recommendations will lead to a harmonization among the authorities of the EU member states and how they will assist the manufacturers of medicinal products in the timely implementation of the requirements of the Guideline ICH Q3D.
A new Annex is planned for the EU Guidelines to Good Manufacturing Practice: Annex 21 on "Importers of Medicinal Products". The concept paper was published on 13 May 2015. The consultation process ended in August 2015. The paper did not provide much information and the first draft of the new Annex is expected soon for public consultation. This new document was triggered by the discussions on the requirements for the import that took place in the course of the revision of Annex 16 (Certification by a Qualified Person and Batch Release). The future Annex targets importers and is supposed to cover requirements for the following import activities that are not covered by other GMP regulations so far:
- incoming goods
- storage of unreleased or of released batches
- sampling for the EU analysis
- EU analysis (exception: imports from MRA countries)
There also was a concept paper published on Annex 1 of the EU Guidelines to Good Manufacturing Practice (Manufacture of Sterile Medicinal Products) (issued on 2 February 2015). Public consultation ended in March 2015. A first draft of the revised Annex is also expected soon for public consultation. The revision is not supposed to create new expectations, but it will contain a lot of adjustments.
- implementation of principles of the concepts of ICH Q8, Q9, and Q10
- adaptation to international regulations (FDA Aseptic Guide)
- clarification of requirements that
- are so far controversial or ambiguous ("filter testing after sterilisation")
- applicability to non-sterile products (clean room classes) based on QRM
- design of new technologies for companies, equipment and processes
- acceptance of the revision of Pharm. Eur. Monograph for WFI (manufacture by means of reverse osmosis coupled with other technologies)
Recommendation
22/23 January 2025
HPLC Data Integrity - Live Online Training
Annex 17 of the EU Guidelines to Good Manufacturing Practice (Real Time Release Testing) is to be modified completely. The revised document was published on 15 September 2015, public consultation ended on 11 December 2015. The change of name alone signalises the reorientation. In the end, the current Annex 17 "Parametric Release" is restricted to be used for the routine release of products sterilised in the final container without sterility tests on the basis of sterilisation parameters. Now the revision shall also implement the principles of the concepts of ICH Q8, Q9 and Q10. A real time release approach will be part of the authorisation in future. Then certification and release of a batch can be based on the following information: monitoring and control of critical process parameters and relevant material attributes, sufficient product knowledge and process understanding and a combination of in-process-monitoring and controls that provide sufficient data. This would justify a batch release without the tests being repeated on a sample of the finished product.
The real time release approach must contain a contingency procedure in case of a sensor or equipment failure. It is not acceptable to perform an additional test on a product (active substance or finished product) yielded by an undesired or unacceptable result as determined by the RTRT approach. This means it is not possible to test the release into a product. It can be accepted, however, under certain conditions to perform an additional test on a product, for instance in the case of failure of important sensors or equipment. A periodic risk assessment of the approach is important ("continued assurance of product quality").
But the parametric release has not disappeared completely. One section describes the use of parametric criteria for the routine release of terminally sterilised products.
The US Food and Drug Administration (FDA) has started an initiative for the use of so-called Quality Metrics for the planning of its risk-based inspections. A first draft was published in July 2015 for comments by associations and industry. After coming into force the FDA wants the manufacturers to communicate defined quality metrics to the US authority via an electronic portal. The FDA will then calculate specific statistics which are supposed to allow a risk-based control and planning of the FDA inspections. Eventually, the FDA requires all companies that produce, prepare, process, assemble or distribute a medicinal product for the US market or that use an active pharmaceutical ingredient for such a medicinal product to provide the data. According to the FDA the Quality Control Unit - QCU generally is the unit supposed to compile the reports. The data will then have to be submitted on request.
Author:
Wolfgang Schmitt
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas Quality Assurance, GMP and GDP.
