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During the 2 European GMP Conference in Heidelberg, Germany, in the summer of 2007, the European Medicines Agency (EMEA) as well as the US Food & Drug Administration introduced their road map for the coming years to attendees of the conference. What was then supposed to change, and what has really been changed since then?

The changes in Europe

In Europe, for instance, risk management has been gaining in importance in the meantime. In addition to the implementation of ICH Q9 (Quality Risk Management) as Annex 20 of the EC GMP Guide, the subject also found its way into the European authority SOP "Compilation of Community Procedures" (key word risk based inspections). It is also supposed to be included in part II of the EC GMP Guide (GMP for APIs).

Another important issue is "Dedicated Facilities", affecting items 5.18/5.19 and 3.6 of the EC GMP Guide. Besides a concept paper there have been several drafts relative to dedicated facilities. Key elements of the first drafts were:

  • Indication of types of products (Cytotoxics and Cytostatics, Betalactam antibiotics, Radiopharmaceuticals, BCG vaccines and so on) for which dedicated and self-contained facilities should be mandatory
  • Types of products which, according to a risk analysis, could be produced on a campaign working basis
  • Factors to be considered within the risk analysis

In January 2008, the EMEA published an interim report on the current state of revision. This report states that the GMP/GDP Inspectors Working Group is unanimous that there will be a list of substances for which a dedicated facility is mandatory. For other products it is supposed to be possible to base this decision on a risk analysis depending on the physico-chemical risk. The drafting group is currently developing a table intended to define a high physicochemical risk in more detail.

Apparently it is planned to submit the revised GMP Guide chapters to the European Commission at the end of 2008; public consultation can be expected to start at the beginning of 2009.

But there are also further plans for changes, which are currently either in a draft phase or already finalised. Finalised are

  • Annex 1 (Sterile Products): The revised version will come into operation in March 2009 and March 2010 ("Capping"). The changes relate more strongly to EN/ ISO 14644 and to the FDA Aseptic Guide.
  • Annex 3 (Radiopharmaceuticals) and Annex 7 (Herbal Products): The revised guides will also become effective on 1 March 2009.

In a draft stage are currently revisions of

  • Annex 2 (Biological Products)
  • Annex 6 (Medicinal Gases)
  • Annex 11 (computerised systems)
  • Annex 13 (Investigational medicinal products) and
  • Annex 14 (Blood Products).

The changes in Annex 11 will also affect chapter 4 of the EC GMP Guide (Documentation). A draft is available already.

Moreover, chapter 5 of the European GMP Guide is currently also being revised. Changes are concentrating on Qualification of suppliers: Until now the GMP Guide (chapter 5.26) referred only to the testing of starting materials. Now this obligation is to be extended to include active pharmaceutical ingredients (APIs) - with a note that only APIs are to be used that are produced according to GMP. To achieve harmonisation between all member states, the requirements on testing of starting materials will also be revised.

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There is also a new draft regarding "Variation Regulations":
An important goal of the regulation is to further decrease the overall number of variations procedures. It is supposed to enable the competent authorities to concentrate on those changes that will in fact impact quality, safety or efficacy. For certain, less severe changes it is planned to introduce a system with annual reports - similar to the system already established in the US. These changes will not have to be approved in advance and should be notified within a 12 months period after their implementation. This would also mean a tremendous relief for the pharmaceutical industry, especially with regard to changes concerning the continuous improvement of manufacturing processes.

In addition there are a number of new requirements concerning the classification of changes. It is also supposed to be possible to propose a reference authority for changes to multiple authorisations. Under certain conditions changes can be grouped and submitted to the authorities in a single notice.

And what is new in the US?

In the Federal Register, the FDA informed about changes to the cGMP rules for medicinal products on 8 September 2008. These changes will come into force on 8 December 2008. Next to a summary, the announcement includes a total of seven further parts: The most interesting ones are parts 1 to 3: Background, the summary and the comments on the original draft document with FDA's answers.

In the summary, the FDA announced that the changes are just one part of the entire revision process for updating the cGMP rules. In a later passage, these changes are announced as efforts to harmonise the cGMP rules with other FDA regulations (the text mentions the Quality Systems Regulation for medical devices) and other GMP regulations (explicit mention of EC GMP).

The changes mainly affect aseptic processing, the implementation of the 4-eyes principle, the use of asbestos-containing filters. Minor changes without relevance for the contents complement the main changes mentioned. The part titled "Background" explains the history that led to the now finalised changes.

Regarding aseptic manufacture, the following paragraphs have been changed:

  • § 211.113(b) - changes concern the validation of the aseptic process for the prevention of microbiological contaminations
  • § 211.67(a) - refers to the sterilisation /sanitisation of equipment
  • § 211.84(d)(6) - affects the microbiological tests performed prior to the use of primary packaging materials
  • § 211.94(c) - validation of depyrogenisation of primary packaging materials and
  • § 211.110(a) - bioburden tests within the framework of in-process controls

Especially the changes to § 211.113(b) are meant to harmonise the FDA requirements with Annex 1 to the EC GMP Guide.

The ban on asbestos-containing filters resulted in changes to §§ 210.3(b)(6) and 211.72. As a reaction to comments on the first revision draft, the passage "the use of an asbestos- containing filter is prohibited" has now been included. Furthermore, the update reflects the state of the art regarding the loss of fibres in filters and the indication of the pore size.

The changes regarding the implementation of the 4-eyes principle ("verification by a second individual") refer to the use of computerised systems instead of a second pair of eyes. This affects a whole number of paragraphs. For example, § 211.68 has been extended by a section (c) now allowing the use of a computerised system instead of a second individual. Of course, this also has consequences for other paragraphs requiring this 4-eyes principle:

  • §§ 211.101(c) and (d) - charge-in of components and containers), § 211.103 (calculation of yields)
  • § 211.182, - equipment cleaning and maintenance
  • § 211.188(b)(11) - batch production and control records

for which reason they will also be adapted.

The "minor changes" concern §§ 211.82(b), 211.84(c)(1) and (d)(3), as well as 211.160(b)(1). The changes serve the purpose of clarification without affecting the contents.

Some of the comments by industry on the original draft and FDA's answers to them that resulted in this final version are also quite interesting. Among other things, the industry reminded the FDA of their fear that the Agency's reviewers and GMP inspectors might lack clarity and consistency in their understanding of the new changes. The FDA replied that it understands this fear and intends to respond to it with adequate training of the group of persons in question.

Four comments prevented among others even the revision of 21 CFR 211.48(a) ("Plumbing"). The original requirement that potable water must be up to EPA (Environmental Protection Agency) standards was intended to be changed in order to harmonise it with other regulations (e. g. those of the EU). The wording should be "safe for human consumption". However, according to the comments, this wording was not prescriptive enough. Within the framework of further updates of the cGMP rules, this question regarding water relating to water qualities used as a component in medicinal products will be taken up again.

Alike its European counterpart, the US authority also pays more attention to quality risk management. For the FDA the 2006 Quality System Guidance serves as a bridge between the cGMP Regulations from 1978 and the quality systems for the 21st century. While cGMP is more concerned with the technical aspects of pharmaceutical manufacturing, modern quality management puts greater emphasis on:

  • Risk analysis
  • Risk management
  • Preventive actions
  • Continual improvement.

The industry is also paying close attention to the next steps regarding the Draft Guidance Process Validation. The bottom line of the (still) valid Process Validation Guideline from 1987 is its focus on full-scale-replication. In the FDA's view, the Compliance Policy Guide 7123c.08 is an interim step towards the new Validation Guidance. It no longer requires process validation prior to approval. But process validation has to be completed prior to distribution.

According to the authority, validation will be regarded as a "life cycle approach" in the revised Process Validation Guidance - including the following three steps:
1. Design (development phase)
2. Confirm/Qualification (commercialisation phase) and
3. Monitor and Assess (maintenance phase)

And manufacturers can define the number of runs themselves - "scientifically based". Requalification and revalidation are part of the maintenance phase. Life cycle will also mean that development leads to process understanding and to the corresponding sources of variability.

The FDA also revised some Guidances to Industry, e.g. regarding beta-Lactam Penicillin Contamination and Penicillin detection and GMPs for Phase I IND Clinical Supplies.

Enforcement Trends of the FDA - Trends concerning Realisation of Inspections

The FDA performs about 200 foreign FDA inspections every year. In 2005, 204 inspections were conducted. In 100 cases, the authority observed deficiencies of so-called "moderate significance", i.e. deficiencies which the concerned firms commonly take care of themselves. Twelve inspections led to further measures by the FDA - such as "regulatory actions in form of warning letters, seizure or injunction".

The analysis of the inspections shows the following most frequently objected cGMP deficiencies:
1. Lab controls (211.160)
2. Validation of production and process controls(211.100)
3. Cleaning equipment (211.67)
4. Batch production records (211.188)
5. Quality Control responsibilities (211.22)
6. Stability (211.166)
7. Batch release testing (211.165)
8. Record review/investigation (211.192)
9. Complaint investigation (211.198)

According to the FDA, typical cGMP problem areas identified during foreign inspections were:
1. Having and following sound lab SOPs; documenting results, testing stability
2. Investigating complaints/issues fully
3. Following production SOPs
4. QC not exercising real oversight
5. Validating manufacturing processes properly

An overview of the GMP deficiencies at drug and API manufacturers' sites further showed that "old friends" such as Failure/OOS Investigations, Equipment Cleaning and Cleaning Validation, Lack of/Inadequate SOPs top the list.

Moreover, the main reasons for drug recalls indicated by the analysis (data from October 2005 to September 2006) also provide a real good insight:

  • Sub-potent (single-ingredient drugs)
  • Defective container
  • Impurities/degradation
  • Lack of assurance of sterility
  • cGMP deviations (not specifically identified)
  • Correct labeled product in incorrect package
  • Microbial contamination of non-sterile products (tied with)
  • Non-Sterility
  • Failed USP Dissolution Requirements
  • Stability
  • Super-potent (single-ingredient drug)

Developments with an impact in Europe as well as in the US

On 4 June 2008, the International Conference on Harmonisation (ICH) adopted the Step-4 version of the Guideline ICH Q10 "Pharmaceutical Quality System", and now it has also made the document available to the public. With this, the guideline is now harmonised in Europe, the US and Japan. The authorities in the three regions, i.e. the EMEA/European Commission in Europe, the FDA in the USA and MHLW in Japan, are now required to include this regulation in their respective legislative/ordinance procedures.

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Co-operation between the European and the American authorities EMEA and FDA are also supposed to be intensified. As a result of a meeting held under the auspices of the Transatlantic Economic Council, a co-operation at the level of administrative practices and guidelines was agreed. The new cooperation covers four different areas:

  • Quality and inspection
  • Pharmacovigilance
  • Scientific collaboration
  • Guidelines, format harmonisation and electronic submission

Conclusion

A lot has happened in the area of GMP since the GMP Conference was conducted in 2007 - and not everything found the support from the industry. For instance, changes regarding the subject "Capping" in the Annex 1 are still in discussion. Further, the planned changes with regard to the Annexes and the chapters 3, 4 and 5 of the EC GMP Guide will lead to discussions. Industry hopes for easement from the revision of the Variation Regulation though.

Regarding FDA everyone is waiting for the revision of the Process Validation Guideline. It will also be interesting to see in the EU as well as in the US how industry will implement ICH Q10. And it further remains to be seen what the announced intensified co-operation between EMEA and FDA really will look like.

Author:
Sven Pommeranz
CONCEPT HEIDELBERG

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