◆  Ensuring the data integrity of cloud service providers (08-May-19 ECA)

The introduction of cloud services into the GMP environment increases. The cost factor dominates the discussion; however, specific risks need to be taken into consideration. Especially the issue of data integrity in cloud applications is not to be underestimated. What agreements need to be included in contracts with cloud service providers in order to ensure data integrity?

The necessity for contractual agreements is laid down in chapter 7 "Outsourced Activities" of the EU GMP Guidelines as well as in Annex 11 "Computerized Systems" of the guidance. The following are requirements for contractual agreements between a Regulated User (RU) and a Cloud Service Provider (CSP) which are meant to ensure the integrity of data (in motion and at rest). These requirements cannot explicitly be found in the EU GMP Guidelines, they should however be considered as useful:

  • Data transfer should only occur in encrypted form and in a way which ensures that the data being transferred are complete and unchanged.
  • CSP handling sensitive data or data with high availability requirements must have a certified ISMS (Information Security Management System) in place (e.g. as per DIN 27001).
  • CSP handling sensitive data or data with high criticality must submit to penetration testing in the course of their qualification.
  • Sensitive or critical data may only be stored in encrypted (or pseudonymized) form.
  • A deployment model should be chosen based on criticality. Private or community cloud models should be chosen rather than a public cloud for sensitive data.
  • Sharing data with a third party (e.g. subcontractors), e.g. providing infrastructure (storage space for backups, redundant computing power, etc) should be prohibited or dependent on the RU's approval.
  • The deletion of data must be fully guaranteed.
  • It must be possible to export data in a way that allows RUs to switch CSPs or get the data back on premise.
  • Only a limited, specifically selected and qualified group of people from the CSP should be able to access the data.
  • If data has been encrypted, the key management should lie with the RU.
  • The CSP informs the RU about changes which might impact the application or database. A notification of change with release note is expected, ideally issued before the actual implementation of the change so that the RU may check the effects of those changes, if necessary.


◆ New WHO Draft for GDP Guidance (23-May-19 ECA)

The World Health Organization WHO plans to revise its Good Storage and Distribution Practice guidelines. During the 53. WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP; October 2018), the Expert Committee recommended the consolidation of the Good Storage Practices and the Good Distribution Practices for pharmaceutical products and the elements of the Good Distribution Channel Guidance into one document. A draft for comments was posted on the WHO Medicines website under Current Projects.

In contrast to other international guidelines like those from PIC/S, the new document has not been aligned with the structure of the EU-GDP Guidelines. It comprises 21 chapters and in chapter three a comprehensive glossary. The scope is rather broad; the guideline "is intended to be applicable to all persons and outlets involved in any aspect of the storage and distribution of medical products from the premises of the manufacturer of the product to the person dispensing or providing pharmaceutical products directly to a patient or his or her agent." That includes all parties involved in trade, storage and distribution, like for example:

  • Manufacturers
  • Wholesalers
  • Brokers and traders
  • Suppliers
  • Distributors
  • Logistics providers, transport companies and forwarding agents

The new guidance does not necessarily call for a designated Responsible Person like EU-GDP does. However a "designated person(s) should be responsible for recalls" (chapter 10) and chapter 13 (Stock Control and Rotation) mentions a "person responsible for quality".


◆  WHO plans Inclusion of environmental Aspects in GMP (29-May-19 ECA)

The World Health Organization WHO has published a draft document on "Environmental Aspects of GMP: points to consider for manufacturers and inspectors in the prevention of antimicrobial resistance".

With this working document the WHO plans to include the topic of waste and wastewater management into their GMP Guidance: it "addresses the current needs for guidance on how GMPs should be implemented to waste and wastewater management for production of antimicrobials, with a focus on Critically Important Antimicrobials."

This initiative could raise concerns with national competent authorities and within industry. The underlying problem is that most active substances (APIs) are produced in countries with weak environmental legislation. An appropriate initiative would be advisable.  The WHO therefore means well, but is perhaps wrong to link this to GMP. One will see what the feedback will be from those who have the World Health Organization's permission to do so.

◆  New FDA Guideline: Quality Aspects for Continuous Manufacturing (13-Mar-19 ECA)

In February 2019, the FDA published a new draft guideline that addresses quality aspects in the continuous manufacturing of medicinal products. It covers topics related to development, process validation, marketing authorisation and routine production.

The FDA sees continuous production as the most important tool in the modernisation of the pharmaceutical industry. In a statement released at the same time by FDA Commissioner Scott Gottlieb and CDER Director Janet Woodcock, there is meanwhile mention of five continuously manufactured products (from four companies) that have already been authorised. Four years ago it was only one authorised product. In total, twenty companies are working with the FDA on continuous manufacturing. These are both original and generic manufacturers. In order to further support the pharmaceutical industry, the present guideline has been developed. The development of an ICH guideline for continuous manufacturing of medicinal products was also initiated and its completion is planned for 2021.

The draft guideline entitled "Quality Considerations for Continuous Manufacturing" is primarily aimed at manufacturers of solid medicinal products or small molecule medicinal products. Basically, the guidelines can also be used for the production of biologics, but these are not the focus of the paper.

The FDA defines a continuous process as a process consisting of at least two connected Unit Operations to which material is continuously fed and from which material (product) is continuously removed. According to the FDA, conventional batch processes consist of a sequence of individual process steps. Since the integrated, continuous procedure is new for the pharmaceutical industry, the new guideline describes the key elements that must be considered in continuous processes. Those elements are covered in the individual chapters:

A. Key Concepts of Continuous Manufacturing
1. Process Dynamics
2. Defining Batches for Continuous Manufacturing Processes

B. Control Strategy
1. Input Material Control
2. Process Monitoring and Control
3. Material Diversion
4. Real Time Release Testing
5. Specification
6. Equipment
7. System Integration, Data Processing, and Management

C. Process Validation
D. Additional Pharmaceutical Quality System Considerations
E. Scale-Up
F. Stability
G. Bridging Existing Batch to Continuous Manufacturing

In contrast to conventional batch processes, continuous processes are dynamic. In order to be able to characterize the process flow, it is necessary to determine the residence-time distribution (RTD). RTD is a probability distribution that describes how long a mass remains in the process. It can be determined by tracer studies, by online measurement of certain product properties and/or by mathematical methods (Process Modelling).

A very important aspect of the continuous process is the control strategy. The key elements for this are: control of input materials, process monitoring, material diversion, real-time release testing (RTRT), specification and process equipment.

Since continuous processes must be continuously "fed" with input materials, their flow behaviour plays a much greater role. This can lead to additional material properties having to be specified, e.g. particle size distribution or density of APIs or excipients.

Ideally, a continuous process is in the so-called "state-of-control". However, there will always be situations where this is not the case, e.g. due to incidents, start-up or shut-down of the process. Here, it has to be ensured that non-compliant material is diverted depending on the severity and duration of the failure and the process dynamics. Unexpected defects that lead to the diversion of product should be investigated before the batch continues to be used.

Through the use of PAT and the associated collection of in-process data, the establishment of a real-time release is possible (RTRT). According to the FDA, this is a "can" and not a "must" for continuous processes, but it is recommended.

According to FDA CFR, a specification is required for finished medicinal products. The establishment of specifications for continuously manufactured products should follow the requirements of ICH Q6A and B. The FDA considers the data generated within the scope of an RTRT to be more meaningful than data determined within the scope of a final and offline testing of the product. Nevertheless, the specification should include offline test methods and acceptance criteria in order to be able to perform stability tests at a later time.

The FDA expects the performance of equipment used for continuous production to decline over time. To prevent this, additional aspects of qualification, maintenance and cleaning must be considered. The qualification of equipment must cover both individual manufacturing steps and the integrated overall process. Qualification should consider expected conditions (flow rates, pressures, speeds, duration). The diversion of non-compliant material should also be checked during qualification. The Quality Unit should establish acceptance criteria for the performance of equipment.

The cleaning procedure should be developed by monitoring materials during and after manufacturing. Residues in the equipment (in pipes, filters, etc.) must be evaluated.

Since continuous processes must be controlled in real time, a great amount of data is generated in a very short time, which must be evaluated in real time in order to make process decisions. According to the FDA, this should be done by an automated system. The FDA considers the design and validation of this system to be particularly critical. The Quality Unit should define in advance which alarms require which actions. The system must also meet the requirements of 21 CFR Part 11.

For the validation of a continuous process, the FDA names the following guidelines: Process Validation: General Principles and Practices as well as ICH Q8, Q9, and Q10. The FDA's three-phase model is also applicable (1 Process Design; 2 Process Qualification; 3 Continued Process Verification), whereby certain qualification steps can shift from phase 2 or 3 to phase 1.

Since the introduction of continuous processes is so fundamental, the manufacturer should evaluate its pharmaceutical quality assurance system and ensure that new issues are covered, such as handling process failures in real time, review of raw materials & in-process materials, change management, CAPA as well as qualification and maintenance for continuous processes.

A chapter is also dedicated to scale-up. Scale-up is possible in three ways: extending process time, increasing flow rates, or increasing both. The FDA sees the lowest risk if the process time alone is increased. In this case, and if other parameters remain unchanged, it may be possible for the manufacturer to map the scale-up within his QA system without sending a supplement to the FDA.

The transition from a conventional batch process to a continuous process is also intended by the FDA as a Prior Approval Supplement (PAS),  usually associated with inspection. In addition, the annex contains a list of definitions and a table indicating where specific information for continuous manufacturing can be provided in a submission (CTD format).

The draft guideline "Quality Considerations for Continuous Manufacturing" can be found on the FDA website.


◆ What are FDA's Plans Concerning New (GMP) Guidelines for 2019? The CDER give answers (27-Mar-19 ECA)

What are FDA's plans concerning new guidelines for calendar year 2019? The Center for Drug Evaluation and Research (CDER) has provided an answer to that question in its list of planned guidelines and/or guidelines to be revised. These documents are presented over five pages, divided into 15 individual categories. These categories partly cover very specific topics, from biosimilars to rare diseases.

Regarding GMP, planned and/or revised guidelines can be found under various sections, e.g. under the categories "Pharmaceutical Quality/Microbiology" and the "CMC" part of the approval. Below, you will find some of the planned/to be revised guidelines with a direct or indirect connection to GMP:

  • Comparative Analytical Assessment to Support a Demonstration of Biosimilarity to a Therapeutic Protein Product
  • Bridging for Drug-Device and Biologic-Device Combination Products
  • Microbiological Considerations for Non-Sterile Drug Products
  • Harmonizing Compendial Standards with Drug Application CMC Approval requirements Using the USP Pending Monograph Process
  • Transdermal and Topical Delivery Systems- Product Development and Quality Considerations
  • Setting Endotoxin Limits During Development of Investigational Oncology Drugs and Biologics
  • Stability Considerations for NDAs, ANDAs and BLAs
  • ANDAs: Stability Testing of Drug Substances and Products Questions and Answers
  • Qualification Process for Drug Development Tools
  • Inspection of Injectable Products for Visible Particulates
  • Quality Considerations for Continuous Manufacturing (CM) 

You can find the complete document entitled "Guidance Agenda New & Revised Draft Guidances CDER Plans to Publish During Calendar Year 2019" on FDA's website.

◆  EMA: Work on Annex 1 (Manufacture of sterile medicinal products) and Annex 21 (Guidance for importers of medicinal products) will continue (17-Oct-18 ECA)

The European Medicines Agency (EMA) has to face challenges like the relocation to Amsterdam and the loss of personnel. Because of this, EMA needs to temporarily scale back or suspend additional activities. EMA has now published a press release and announced the next phase of its Brexit preparedness business continuity plan (BCP), which entered into its third phase. The BCP will help to define core activities related to the evaluation and supervision of medicines.

"EMA will now temporarily suspend or scale back additional activities to ensure that resources can be redeployed so that its core activities can continue without interruption and to the same quality," commented Noël Wathion, EMA's Deputy Executive Director. "Over the next few months, EMA will continue to carefully monitor staff intentions to relocate and the anticipated impact on its activities whilst planning for the critical time period when the Agency will be moving to its new premises in Amsterdam."

Despite the necessary temporary suspension/ scaling back of activities, EMA has defined seven guidelines, which will exceptionally continue during BCP phase 3:

  • Revision of Annex 1 of the EU GMP Guide (H/V) - Manufacture of sterile medicinal products.
  • New Annex 21 of the EU GMP Guide (H/V) - Guidance for importers of medicinal products.
  • Reflection Paper of Good Manufacturing Practice and Marketing Authorisation Holders.
  • Guideline on quality requirements of medicinal products containing a device component for delivery or use of the medicinal product.
  • Good Pharmacovigilance Practice: Pregnancy and Breast Feeding.
  • Revision 6 of Note for Guidance on the evaluation of anticancer medicinal products in man.
  • Guideline on the use of minimal residual disease as a clinical endpoint in Multiple Myeloma trials.

Furthermore, meetings of product-related working parties will continue as scheduled; but all meetings of non-product related working parties have been temporarily put on hold.


◆  Current Questions on Validation of Blend Uniformity - Stratified Sampling (07-Nov-18 ECA)

Validating blend uniformity is a decisive factor for the validation of solid dosage forms. In Europe, there are no regulatory provisions for this. This is different in the USA: according to 21 Code of Federal Regulation (CFR) 211.110, the adequacy of mixing has to be regularly assessed. Until 2013, there was a FDA Draft Guidance which described how to realise this assessment. The FDA withdrew it in 2013 though.

Now, what is today's state of the art with regard to the validation of blend uniformity? To provide guidance on that topic, the ISPE started a Blend Uniformity and Content Uniformity (BUCU) initiative. This initiative was the topic of a webinar organised last year. In the following, please find a few questions and the answers provided by the speaker Dr Gerrit Hauck, today at Basilea Pharmaceutica International AG.

Question 1
In our process of validation, the tolerated standard deviation is derived as acceptance criterion depending on the sample size and mean in accordance with the label claim from the ASTM. Is this procedure acceptable?

Answer 1
As long as you refer to the tables laid down in ASTME2810, this procedure is - as far as I am concerned - correct, however only insofar as you consider a pure random sample.  Stratified Samples require other statistics.

Question 2
Does the approach of validation of mixing remain the same for more than one API?

Answer 2
Usually yes, unless one of the drug substances would be present in very high concentration so that one could argue that a determination of the mixing homogeneity shouldn't be required.

Question 3
Do you apply sampling already in the routine? How will you ensure in practice that samples are taken at 30 sampling locations? Will the samples be combined and should I take more in case that a pill falls off?

Answer 3
Yes, sampling at 20 or 40 sampling locations has to be exactly planned. We usually set the sampling times on the basis of significant events and then distribute the remaining samples according to the period between e.g. the beginning of the batch, change of template and batch end. It is quite not unusual to take more than e.g. 3 samples per locations so that for example a pill that fell off can be replaced. We usually take reserve samples.

Question 4
Will the ISPE recommendation be soon implemented in a guideline?

Answer 4
To my knowledge, the implementation in a guideline is not being planned. Through the publication of the ISPE recommendation, a method aligned with the state of the art is now available so that there is no actually need for a FDA Guideline.

Question 5
Why is the USP provision far less strict than the expectations of the FDA & Co?

Answer 5
In my opinion, many tests traditionally used in the pharmaceutical industry are not particularly demanding. Especially considerations about the risks for consumers are often excluded from the test criteria. Especially in the USA, the scientific debate is moving to more demanding tests.


◆  Classification of GMP Deficiencies - A new Guideline of the PIC/S (27-Nov-18 ECA)

Following the PIC/S Committee Meeting in Chicago (USA) at the end of September 2018, the PIC/S announced that the PIC/S working group had elaborated a new guideline on the classification of GMP deficiencies which is going to be adopted. The work on this paper had already begun in 2012 after the topic "classification of GMP deficiencies" had been discussed during the PIC/S meeting in 2011 in South Africa.

The aim of the new document is to provide harmonisation of GMP deficiencies in GMP inspections across the different inspectorates. Indeed, consistency should be ensured throughout the different inspectorates of countries to define when a deficiency is a critical one and when it is a major one.

The paper is to be seen as a tool which facilitates the risk-based classification of GMP observations. On the one hand, it should support  inspectors in their work and on the other hand it should serve as information for the industry on how deficiencies are classified. To that end, the guideline should include examples and be non-binding so that the responsibility for the extent of a deficiency discovered still remains in the hands of the manufacturer inspected.

Moreover, reflection is ongoing on also taking into consideration GDP deficiencies (i.e. inspection findings from Good Distribution Practice inspections) in the guideline.

The new guideline "Classification of GMP-Deficiencies" - which will carry the number PI 040-01.

◆  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.

◆  PIC/S implements EU-GDP for APIs (02-Aug-18 ECA)

The PIC/S* adopts the Guidelines on the principles of Good Distribution Practice for active substances for medicinal products for human use (PI 047-1). It transposes the EU Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use for PIC/S purposes. According to a PIC/ news, this "adoption further strengthens harmonisation between PIC/S and the EU". The guidelines are more or less the same with some minor editorial differences.

Will PIC/S countries (like for example the US) now have to implement EU GDP?

According to the PIC/S GUIDELINES ON THE PRINCIPLES OF GOOD DISTRIBUTION PRACTICE OF ACTIVE SUBSTANCES FOR MEDICINAL PRODUCTS FOR HUMAN USE, "it is up to each PIC/S Participating Authority to decide whether it should become a legally-binding standard."

*The Pharmaceutical Inspection Co-operation Scheme (PIC/S) is a non-binding, informal co-operative arrangement between Regulatory Authorities in the field of Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use. It is open to any Authority having a comparable GMP inspection system. PIC/S presently comprises 52 participating authorities coming from Europe, Africa, America, Asia and Australasia.


◆  Successful ECA, USP and EDQM Joint Conference on Glass packagings (15-Aug-18 ECA)

Together with the industry, the pharmacopeias are currently working on new approaches for the inner surface hydrolytic test and the light transmission test (for amber glass). Additionally, efforts are being made to develop a new description of the autoclave procedure for the glass grains and the surface tests to eliminate ongoing questions associated with the autoclave cycle and to establish a global standard.

At the USP - Ph. Eur. - ECA Joint Conference GLASS meets PHARMA from 6-7 June 2018 in Berlin, Germany, the latest news regarding glass packaging were presented by 13 speakers from FDA, EDQM, USP and Industry, including:

  • An Update of USP General Chapters <660>, <1660>, including proposed revisions regarding the hydrolytic resistance test and the light transmission test
  • An Update of Ph. Eur. Chapter 3.2.1 (specific topics: delamination / hydrolytic resistance)
  • Glass Delamination (What is delamination – What‘s it like?) and Product Recalls caused by Delamination
  • Glass Particles (Particle Contamination in Parenterals) including USP´s approach to glass particulates: Proposed New General Chapter <667> Sub-Visible and Visible Particulates in Packaging and Manufacturing Components and Systems
  • Risk Evaluation of Elemental Impurities (EIs) from Glass in view of ICH Q3D and mitigation strategies to reduce extractables with surface treatment and coatings (for example by siliconization of the container inner surface)
  • Glass formulations with enhanced chemical stability - for example Aluminosilicate glass (e.g. Valor Glass®) which is not covered by the pharmacopoeias yet.
  • New approaches to prevent breakage in filling lines using an innovative technology (SmartSkin©) in regard to:
  1. The identification of process steps with high (mechanical) stresses,
  2. The optimization of process / filling line,
  3. The increase in product yield through reduction of defect rates.

These topics were highly discussed by the audience and the participant´s comments will now be considered during the revision process of the pharmacopoeias regarding the chapters on glass packaging materials.


◆  New Q&As on Chapter 3 of the EU-GDP Practice Guide (Premises and Equipment) (25-Sep-18 ECA)

On the GDP Association Webpage a section has been set up a while ago dealing with frequently asked questions (FAQs). Now a set of new FAQs has been published about Chapter 3 on Premises and Equipment.

For example, answers to the following questions are provided:

  • Which products can be stored in the warehouse with segregation based on a computerised system? And which products do need physical segregation?
  • How can receiving and dispatch bays be designed to protect products from prevailing weather conditions?
  • For premises and storage facilities, adequate cleaning programmes should be in place. How can this be realised?
  • Can I take personal medication into the storage area?
  • Where should we put temperature monitoring equipment?
  • What is "key equipment"?

Answers to these and other questions are provided in the FAQs on GDP.