FDA publishes Final Guideline on GMP for Combination Products

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version of the FDA Guideline for Combination Products?

http://www.gmp-compliance.org/enews_05738_FDA-publishes-Final-Guideline-on-GMP-for-Combination-Products_15649,16021,15963,Z-VM_n.html

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version? In the following you will find an overview:

The final guideline has expanded to now 59 pages (draft: 46 pages). And also the number of footnotes increased from 85 (draft) to 147 (final).

In the table of content there are one new subchapter (II B  Quality and Current Good Manufacturing Practice) and one new chapter (VII Glossary). Subchapter III C was expanded to definitions and terminology. In the following the table of content is listed:

I. Introduction

II. Background
A. Definition of a combination product
B. Quality and Current Good Manufacturing Practices
C. Overview of the final rule
D. The role of the lead center and other agency components

III. General Considerations for CGMP Compliance
A. Demonstrating compliance
B. Investigational products
C. Definitions and terminology
D. What CGMP requirements apply to a product or facility?
E. Control of changes to a combination product

IV. What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)?
A. Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1)
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)
C. Combination products that include biological products and HCT/Ps

V. Application of CGMP requirements to specific types of combination products
A. Prefilled syringe
B. Drug-coated mesh
C. Drug Eluting Stent (DES)

VI. Contact Us

VII. Glossary

VIII. References

In the introduction it is explicitly stated, that “The final rule did not establish any new requirements”. In a footnote the guideline gives an explanation why the term “legacy” combination product has not been used.

In the new subchapter II B  (Quality and Current Good Manufacturing Practice) the guideline mentions, that “the core requirements embedded in these regulations provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. This includes establishing a strong quality management system, using appropriate quality raw materials, establishing robust manufacturing and control procedures based on sound design principles, and detecting and investigating product quality deviations. In addition, these regulations call for ongoing assessment of systems and the implementation of corrective actions where appropriate”.

The final document introduces in Section C the new term “CGMP operating system”. This means the operating system within an establishment that is designed and implemented to address and meet the current good manufacturing practice requirements applicable to the manufacture of a combination product. A clarification about constituent parts of cross-labeled combination products is also implemented. Further, there is a new passage about the choice of the GMP-approach (QS regulation vs drug CGMPs) also regarding a streamlined approach and for companies manufacturing different products. Completely new is the passage with the title “Documentation of CGMP Approach”. Here you can also find hints that manufacturerers with products that have been on the market since before GMP for Combination Products (21 CFR 4) came into operation, have to be compliant too. The guideline requires that the information about the “CGMP operating system” should be shared with FDA investigators in the beginning of an inspection.

In the “Demonstrating compliance” subchapter (III A) there is additional information about crossreferenced approaches (21 CFR 820 vs 21 CFR 211 and vice versa). For investigational products (III B) you can find more detailed information about exemptions from part 820 regarding 21 CFR 820.30 (Design).

In the Definition and terminology section (III D) there are amendments regarding container closure aspects and kits. Section III D (What CGMP requirements apply to a product or facility?) details the responsibility of the owner of a combination product and CAPA procedures in shared facilities.

In section III E. (Control of changes to a combination product) information for single entity and co-packed combination product manufacturers has been amended. The passages in IV A (Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) with regard to 21 CFR 820 about Management Responsibility, Design Controls, Purchasing Controls and CAPA have been extended – including examples – and “modernised”. Terms like quality oversight and QTTP are now mentioned there. Vice versa the passages with regard to 21 CFR 211, 211.84. 211.103, 211.132, 211.137, 211.165, 211.166, 211.167, and 211.170,  (IV B  Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)) have also been extended – likewise with examples – and have been “modernised” as well (e.g. parametric release is mentioned).

In the example about prefilled syringes (V A) one can find an amended passsage about Design Controls and a new section about Design History File. In the example about drug-coated mesh (V B) there has also been included a new section about Design History File. In the drug eluting stent example (V. C) there are amendments in the section about 21 CFR 211.184, 21 CFR 211.103 and 21 CFR 211.170. Furthermore all examples comprise editorial changes.

Completely new is the chapter VII (Glossary). The number of references (Chapter VIII) increased to 31 (draft: 19).

Summary:
There are a lot of changes from the draft to the final document. One chapter (Glossary) and a subchapter ( Quality and Current Good Manufacturing Practices) are new, but there are also new passages and amendments in the final document. Helpful are the examples that have been integrated.

Please also see the Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products for more details.

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GMP’s for Early Stage Development of new Drug substances and products

GMP’s for Early Stage Development of New Drug substances and products

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The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 54–58.

From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing change into synthetic processes, dosage forms, analytical methods, and specifications. The quality system implemented during this early phase should take into account that these changes and adjustments are intrinsic to the work being performed prior to the determination of the final process and validation of the analytical methods during later stages of development.

FDA guidance is already available on GMP requirements for phase 1 materials. (See Org. Process. Res. Dev. 2008, 12, 817.) Because many aspects of phase 2a clinical studies are similar in their scope and expectations, the working group feels there is an opportunity to extend this guidance across all early phase studies. Because products and processes are less well understood in the early phases of development, activities should focus on accumulating the appropriate knowledge to adequately ensure patient safety. Focusing on this area should ensure that beneficial therapies reach the clinic in an optimum time scale with minimal safety concerns.

A follow-up article ( Pharm. Technol. 2012, 36 (7), 76−84) describes the working group’s approach to the subject of Analytical Method Validation. Their assessment has uncovered the need to differentiate the terms “validation” and “qualification”. Method qualification is based on the type, intended purpose, and scientific understanding of the type of method in use. Although not used for GMP release of clinical materials, qualified methods are reliable experimental methods that may be used for characterization work such as reference standards and the scientific prediction of shelf life. For example, in early development it would be sufficient for methods used for in-process testing to be qualified, whereas those methods used for release testing and for stability determination would be more fully validated.

In early development, a major purpose of analytical methods is to determine the potency of APIs and drug products to ensure that the correct dose is delivered in the clinic. Methods should also indicate stability, identify impurities and degradants, and allow characterization of key attributes. In the later stages, when processes are locked and need to be transferred to worldwide manufacturing facilities, methods need to be cost-effective, operationally viable, and suitably robust such that the methods will perform consistently. irrespective of where they are executed.

The authors advocate that the same amount of rigorous and extensive method-validation experiments, as described in ICH Q2, “Analytical Validation”, is not needed for methods used to support early stage drug development. For example, parameters involving interlaboratory studies (i.e., intermediate precision, reproducibility, and robustness) are not typically performed during early phase development, being replaced by appropriate method-transfer assessments and verified by system suitability requirements. Because of changes in synthetic routes and formulations, the impurities and degradation products formed may change during development.

Accordingly, related substances are often determined using area percentage by assuming that the relative response factors are similar to that of the API. As a result, extensive studies to demonstrate mass balance are typically not conducted during early development.

Detailed recommendations are provided for each aspect of method validation (specificity, accuracy, precision, limit of detection, limit of quantitation, linearity, range, robustness) according to the nature of the test (identification, assay, impurity, physical tests) for both early- and late phase development. These recommendations are also neatly summarized in a matrix form.

Above text drew attention to a series of articles from the IQ Consortium (International Consortium on Innovation and Quality in Pharmaceutical Development) on appropriate good manufacturing practices (GMP) for the early development phases of new drug substances and products. The fifth article in this series(Coutant, M.; Ge, Z.; McElvain, J. S.; Miller, S. A.; O’Connor, D.; Swanek, F.; Szulc, M.; Trone, M. D.; Wong-Moon, K.; Yazdanian, M.; Yehl, P.; Zhang, S.Early Development GMPs for Small-Molecule Specifications: An Industry Perspective (Part V) Pharm. Technol. 2012, 36 ( 10) 86– 94) focuses on the setting of specifications during these early phases (I and IIa).

Due to the high attrition rate in early development, the focus should be on consistent specifications that ensure patient safety, supported by preclinical and early clinical safety studies. On the basis of the cumulative industry experience of the IQ working group members, the authors of this paper propose standardized early phase specification tests and acceptance criteria for both drug substance and drug product. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications, but which may be performed to collect information for product and process understanding or to provide greater control.

The drug substance used in preclinical animal studies (tox batch) is fundamental in defining the specifications for an early phase clinical drug substance (DS). Here, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities and processing capabilities. At this stage the emphasis should be on ensuring the correct DS is administered, determining the correct potency value, and quantitating impurities for toxicology purposes. For DS intended for clinical studies, additional testing and controls may be required; the testing may be similar to that for the tox batch, but now with established acceptance criteria. For these stages the authors propose a standardized set of DS specifications, as follows.

Description	range of colour
identification	conforms to a reference spectrum
counterion	report results
assay	97–103% on a dry basis
impurities	NMT 3.0% total, NMT 1.0% each
unidentified	NMT 0.3%
unqualified	NMT 0.15%
mutagenic	follow EMA guidelines (pending ICH M7 guidance)
inorganic	follow EMA guidelines (pending ICH Q3D guidance)
residual solvents	use ICH Q3C limits or other justified limits for solvents used in final synthetic step
water content	report results
solid form	report results
particle size	report results
residue on ignition	NMT 1.0%

These may be altered in line with any specific knowledge of the compound in question. For example, if the DS is a hydrate or is known to be hygroscopic or sensitive to water, a specified water content may be appropriate. Of particular note is the use of impurity thresholds which are 3 times higher than those defined in ICH Q3 guidelines. Q3 was never intended to apply to clinical drugs, and higher thresholds can be justified by the limited exposure that patients experience during these early stages. Mutagenic impurities are the exception here, since in this area the existing official guidance does cover clinical drugs.

The fourth article in the series(Acken, B.; Alasandro, M.; Colgan, S.; Curry, P.; Diana, F.; Li, Q. C.; Li, Z. J.; Mazzeo, T.; Rignall, A.; Tan, Z. J.; Timpano, R.Early Development GMPs for Stability (Part IV) Pharm. Technol. 2012, 36 ( 9) 64– 70) considers appropriate approaches to stability testing during early clinical phases. Appropriate stability data at suitable storage conditions are required to support filing the clinical trial application (CTA/IND/IMPD) and use of the clinical material through the end of the clinical study. Several factors from business, regulatory, and scientific perspectives need to be taken into account when designing early stability studies, such as the risk tolerance of the sponsoring organization, the inherent stability of the drug substance and prior product, process and stability knowledge, the regulatory environment in the countries where the clinical trial will be conducted, and the projected future use of the product.

Often non-GMP DS batches are manufactured first and placed on stability to support a variety of product development activities.In many cases these batches will be representative of subsequent GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. In early development, it is common for the manufacturing process to be improved; therefore, as the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted.

The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability—otherwise not. Typical changes encountered at this stage include changes in synthetic pathway, batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps.

In most cases, these changes will not result in changes in DS stability. Changes to the impurity profile are unlikely to affect stability, since most organically related impurities will be inert. On the other hand, catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents may affect stability; thus, changes to these attributes would typically require the new batch to be placed in the stability program. Similarly, any changes to polymorphic form, particle size, or counterion would warrant extra testing. Packaging changes of the bulk material to a less protective package may require stability data to support the change.

Three approaches to stability data collection are commonly used. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH), and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). A second approach is to use high stress conditions such as a high temperature and high humidity with a short time. A third approach is the use of stress studies at several conditions coupled with modelling. The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

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Ref

http://www.rcainc.com/wp-content/uploads/2014/06/RCA-GMPs-for-Early-Stage-Development-Projects.pdf

http://www.pharmtech.com/gmps-method-validation-early-development-industry-perspective-part-ii

http://www.pharmtech.com/gmps-small-molecule-drugs-early-development-part-i

https://iqconsortium.org/images/Publications/Presentations/GMPs_Workshop_-_Early_Development_Stability_(Industry_Perspective_-_Tony_Mazzeo,_BMS).pdf

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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What are the GMP Responsibilities of the Marketing Authorisation Holders?

The European Medicines Agency (EMA) has published a concept paper to summarise the GMP responsibilities of the Marketing Authorisation Holders (MAH).

http://www.gmp-compliance.org/enews_05618_What-are-the-GMP-Responsibilities-of-the-Marketing-Authorisation-Holders_15367,15360,15355,15618,Z-QAMPP_n.html

The GMP/GDP Inspectors Working Group of the European Medicines Agency (EMA) has published a concept paper to summarise the GMP responsibilities of the Marketing Authorisation Holders (MAH). It is not intended to introduce any new responsibilities on MAHs but to document existing requirements in a better way.

The current EU GMP-Guidelines define in several chapters and annexes GMP tasks and responsibilities of the MAH. However, there seems to be a lack of clarity and understanding as to what these responsibilities actually are in their totality, and what they mean for MAHs at a practical level. All these tasks and responsibilities have now been summarised in this concept paper:

• Chapter 1: responsibility to evaluate the results of the PQR review
• Chapter 7: responsibility to put contracts in place
• Chapter 8: responsibilities concerning quality defects, risk-reducing actions and notification of possible disruption in supply
• Annex 2: responsibility to put contracts in place
• Annex 12: obligations to approve the design of irradiation cycles, and agreeing the location for retention of irradiation cycle records.
• Annex 16: requirement to identify the site and QP responsible for certifying each batch (in the case of multiple sites authorised to manufacture / import / certify the same product) and the statement that the “ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy” lies with the MAH
• Annex 19: responsibilities for ensuring that reference and retention samples are taken, and stored.

The GMP/GDP Inspectors Working Group thinks that the issues outlined above “are not without important consequences. The way in which MAHs are expected to interact with the manufacturing sites registered in a marketing authorisation is not sufficiently clear, given the diverse ways in which the various MAH responsibilities are set out in the EC Guide to GMP, and differing (often complex) supply chains.”

So what is next?

According to the Concept Paper, “It is recommended that the GMP/GDP Inspectors Working Group (GMP/GDP IWG) should produce a reflection paper intended for Part III of the EU GMP Guide or in another appropriate location (e.g. as proposed by the GMP/GDP IWG). This would capture all of the responsibilities that apply to MAH companies to enable manufacturers to comply with GMP. It would also result in a more complete picture of the regulatory environment with respect to GMP in which the MAH operates.”

The deadline for comments on the concept paper is end of November 2016. Comments should be sent to adm-gmdp@ema.europa.eu.

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Annex 16: How a QP should handle unexpected Deviations

In a recent blog of the MHRA, the inspectorate looks at one aspect of the new Annex 16 – the handling of unexpected deviations.

see http://www.gmp-compliance.org/enews_05428_Annex-16-How-a-QP-should-handle-unexpected-Deviations_15432,15354,15367,Z-QAMPP_n.html

In a recent blog of the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), the inspectorate looks at one aspect of the new Annex 16 – the handling of unexpected deviations.

Before Annex 16 was revised, the handling of minor deviations from defined processes was discussed in the European Medicines Agency’s “reflection paper” EMEA/INS/GMP/227075/2008. However, the status of this paper was not always clear, and its use was not consistently applied. Now section 3 of the new Annex 16 provides guidance on when a Qualified Person (QP) may consider confirming compliance or certifying a batch where an unexpected deviation (concerning the manufacturing process and/or the analytical control methods) from the MA and/or GMP has occurred.

Pre-requisites

Before a QP releases a batch these pre-requisites need to be considered:

• All registered specifications must be met! This includes specifications for active substances, excipients, packaging materials and medicinal products with all defined in-process, bulk and finished product specifications. If any registered specification is not met, the QP must not release the batch.
• Only unexpected deviations fall under the scope of section 3. That does also mean that repeated deviations cannot be accepted for certification, because they no longer meet the “unexpected” criteria.
• The deviation must be thoroughly investigated, the root cause determined and the necessary actions defined.
• A risk management process should be used to determine the impact on quality, safety and efficacy.

Quality Management System

Quality Management System failures are not covered by this section. But the quality management system of the manufacturer should maintain a record of which batches have been certified under the respective provisions. And it should also be considered in the management review and annual product quality reviews.

Notification of the Authorities

If the handling of the deviation is in accordance with the Annex 16 restrictions, the competent authority does not need to be informed (see also Chapter 8 of the EU Guide). But manufacturers and importers are required to notify competent authorities of quality problems and non-compliance affecting the Marketing Authorisation (MA).

Please also see the MHRA Inspectorate’s blog for more detailed information.

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Final WHO Guidance Document on Good Data and Record Management Practices

The WHO has just released the  the final version of the important guideline “Good Data and Record Management Practices“.

http://www.gmp-compliance.org/enews_05418_Final-WHO-Guidance-Document-on-Good-Data-and-Record-Management-Practices_15488,15637,Z-COVM_n.html

We recently informed you about the WHO Draft Guidance on Good Data and Record Management Practices. Now, the WHO has just released the  the final version of this important guideline “Good Data and Record Management Practices”.

The final version is sectioned rather similar to the draft version:

– Introduction
– Aims and objectives of this guidance
– Glossary
– Principles
– Quality risk management to ensure good data management
– Management governance and quality audits
– Contracted organizations, suppliers and service providers
– Training in good data and record management
– Good documentation practices
– Designing and validation systems to assure data quality and reliability
– Managing data and records throughout  the data lifecycle
– Addressing data reliability issues
– References and further reading

Although the individual chapters were kept rather unchained the content of these chapters was updated throughout the whole document.

For instance the term “good documentation practices” has now been expanded to “good data and record management practices” and is defined as follows in the glossary:

“The totality of organized measures that should be in place to collectively and individually ensure that data and records are secure, attributable, legible, traceable, permanent, contemporaneously recorded, original and accurate and that if not robustly implemented can impact on data reliability and completeness and undermine the robustness of decision-making based upon those data records.”

Some of the former content has been put into Appendix 1 now: Here you can find expectations and examples of special risk management considerations for the implementation of ALCOA (-plus) principles in paper-based and electronic systems. The tables in this appendix provide further guidance on the implementation of the general ALCOA requirements. In addition, examples of special risk management considerations as well as several illustrative examples are provided of how these measures are typically implemented.

However, these examples should not be taken as setting new normative requirements.

For further information please see the final WHO Guidance on Good Data and Record Management Practices.

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New FDA Draft Guidance ‘Data Integrity and Compliance with cGMP’ published

In the last years, the topic “data integrity” has become a priority for the FDA. Recently, the Agency has published the draft of a Guidance for Industry on the topic which presents the comprehensive opinion of the FDA on data integrity. Read more about the draft of the Guidance for Industry “Data Integrity and Compliance with cGMP”.

http://www.gmp-compliance.org/enews_05311_New-FDA-Draft-Guidance–Data-Integrity-and-Compliance-with-cGMP–published_15555,15527,15062,15064,Z-COVM_n.html

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?
2. When is it permissible to exclude CGMP data from decision making?
3. Does each workflow on our computer system need to be validated?
4. How should access to CGMP computer systems be restricted?
5. Why is FDA concerned with the use of shared login accounts for computer systems?
6. How should blank forms be controlled?
7. How often should audit trails be reviewed?
8. Who should review audit trails?
9. Can electronic copies be used as accurate reproductions of paper or electronic records?
10. 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?
11. Can electronic signatures be used instead of handwritten signatures for master production and control records?
12. When does electronic data become a CGMP record?
13. Why has the FDA cited use of actual samples during “system suitability” or test, prep, or equilibration runs in warning letters?
14. Is it acceptable to only save the final results from reprocessed laboratory chromatography?
15. Can an internal tip regarding a quality issue, such as potential data falsification, be handled informally outside of the documented CGMP quality system?
16. Should personnel be trained in detecting data integrity issues as part of a routine CGMP training program?
17. Is the FDA investigator allowed to look at my electronic records?
18. 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”

\//////////New FDA Draft Guidance, Data Integrity, Compliance, cGMP,  published

GMP/GDP: When will I be inspected by the Authorities?

Various competent authorities are performing inspections. But who is subject to such an inspection?

http://www.gmp-compliance.org/enews_05297_GMP-GDP-When-will-I-be-inspected-by-the-Authorities_15352,15356,15274,15432,Z-QAMPP_n.html

GMP Inspections are carried out at Manufacturer Licence Holders

A manufacturer of medicinal products must meet Good Manufacturing Practice (GMP) standards. These standards are defined in various laws and regulations. In the EU the compliance with these regulations is checked and assessed by the national competent authorities. The overall goal is to have medicinal products of consistent high quality that meet the requirements of the marketing authorisation (MA) or product specification.

If a company supplies product to the USA, the U.S. Food and Drug Administration (FDA) might inspect the site assuring that drugs, medical devices, certain active pharmaceutical ingredients (APIs) and biological products manufactured in foreign countries and intended for U.S. distribution are in compliance with the applicable U.S. law and regulations.

GDP Inspections are carried out at Wholesale Dealer Licence Holders

Good Distribution Practice (GDP) requires that medicines are obtained from the licensed supply chain and are consistently stored, transported and handled under suitable conditions, as required by the MA or product specification. Many of the actors in the supply chain must implement GDP but are not under supervision. The competent authority for GDP will normally not carry out GDP inspections at transport companies (shipping companies) or at airport hubs.

You will also be inspected when you apply for a manufacturer or wholesaler dealer licence and then periodically, normally based on risk assessments. Overseas manufacturing sites are also inspected when medicinal products or certain APIs are imported to the EU.

Types of inspection

Inspections under a risk-based compliance programme

It is the aim of the competent authorities and inspectorates to prioritise regular inspections based on risk assessments. These inspections are generally announced in advance.

GMP inspections may sometimes be carried out with other inspections, such as with GDP, Good Clinical Practice (GCP) or Good Pharmacovigilance Practice (GPvP).

Product-related GMP inspections

Inspectorates may conduct product-related GMP inspections when assessing an application for a marketing authorisation. This inspection checks if the manufacturer complies with GMP. FDA may also carry out these pre-approval inspections. These inspections are generally announced in advance.

Product-related inspections can also be requested by the European Medicines Agency (EMA) for example by the Committee for Human Medicinal products (CHMp) during the pre-application of a centralised marketing authorisation application or the Co-ordination group for Mutual Recognition and Decentralised Procedures – human (CMDh). EMA uses inspectors from EU member states to ensure compliance with GMP principles.

Triggered or For Cause Inspections

Competent Authorities may inspect you if they are informed about possible GMP or GDP breaches for example by a whistle blower, the press/ media or another regulatory authority.

Here, only little or no notification of these inspections is given in advance.

///GMP inspections, Manufacturer Licence Holders

Regulatory Approval Pathways: EU vs US

Regulatory Approval Pathways: EU vs US

Drug Authorization Procedures in the EU 

Sponsors have several options when seeking market approval for a new drug in Europe: a national authorization procedure, a decentralized procedure, a mutual recognition procedure and a centralized procedure. Depending on a product’s eligibility, each of these authorization routes offers different advantages and disadvantages to the sponsor, and these should be considered when setting up the market strategy of a product.

National Procedure

This procedure is used whenever a company wants to commercialize a product in only one EU Member State.

The National procedure is specific to each country. That is, each country within the EU has its own procedures for authorizing a marketing application for a new drug. Sponsors can find information regarding the requirements and procedure of each country on the websites of the regulatory agencies.

ADVANTAGES of National Procedure

There are some advantages in submitting a MAA through this procedure. First, it allows the sponsor to choose which country the company will submit to first. This is especially advantageous when the sponsor can’t afford to go through the centralized or decentralized procedure, due to lack of resources of distribution infrastructure for example. Choosing the country that the sponsor is most familiar with in regards to its regulation can also be an important factor.  The national authorization procedure also allows the sponsor to, further down the line, get his drug approved through the mutual recognition procedure, seeing as one country already approved its drug. Overall, this procedure is less resource heavy than the others, and thus it is the cheapest and safest alternative for a sponsor.

DISADVANTAGES of National Procedure

The disadvantages are obvious, seeing as this procedure only allows the sponsor to commercialize in one single market, cutting potential revenue streams it could have by bringing the drug to more markets.

Centralized procedure

The centralized procedure is a Europe wide authorization procedure, conducted by EMA’s Committee for Human Medicinal Products (CHMP), an organization which has representatives of all Member states, EEA members, patient organizations and health professionals.

When a sponsor applies for drug approval through the Centralized Procedure, two member states are first selected, a rapporteur and a co-rapporteur. These two member states will be responsible for the creation of an evaluation report that will be assessed by the CHMP.  First, a draft report is prepared and sent to the committee for review. The committee prepares a set of questions to send to the sponsor. After receiving a response, further discussions continue and a final evaluation report is arranged, containing a positive or negative opinion. This whole process can take up to 210 days. After the report is completed, it is sent to the European Commission in less than 15 days. The European Commission has the final say on the matter, granting the MA or not after evaluation of the CHMP’s report. The EC’s decision is applicable to all Member States of the European Union and EEA states – Iceland, Norway e Liechtenstein. After approval from the EC, the MA is valid for five years.

The centralized procedure, when it was introduced by Regulation (EEC) no 2309/93, followed the footsteps first established by Directive 87/22/EEC with its concertation procedure , and it was first made obligatory to products made from Recombinant DNA technology, controlled gene expression and monoclonal antibodies.

Afterwards, Regulation (EC) No 726/2004 extended the scope of the procedure to include orphan medicinal products and new active substances for the treatment of acquired immune deficiency syndrome (HIV), cancer, neurodegenerative disorder or diabetes. It went into force in 20th November 2005.

Recital 8 and Point 3 of the Annex to Regulation (EC) No 726/2004 also established that, starting 20 May 2008, the centralized procedure would be obligatory for drug products containing new active substances for the treatment of autoimmune diseases and other immune dysfunctions and viral diseases.

Lastly, regulation EC No 1394/2007 made the procedure compulsory for Advanced Therapy Medicinal products, like gene therapy, tissue engineered and somatic cell therapy products.

Article 3(2) of Regulation (EC) No 726/2004 defines the optional scope of the centralized procedure. It states that the procedure can be followed optionally by medicines that contain a new active substance, or if the applicant shows that the therapeutic entity provides a significant therapeutic, scientific or technical innovation, and it would be in the best interest of public health if it was approved at a community level.

ADVANTAGES of Centralized Procedure

Products authorized through the centralized procedure are granted marketing authorizations that cover all EU member states and the EEA, a big, 500 million user market where the sponsor can potentially recoup the losses from drug development. The drug will be commercialized in all countries with a single, unique brand name.

The convenience of the centralized procedure is however accompanied by fees that are significantly higher than the national procedure’s.

DISADVANTAGES of Centralized Procedure

Also, it is also a very risky, all or nothing procedure. If the CHMP refuses an application, the drug is barred from sale in every EU country, whereas if the sponsor tried another authorization procedure, there was the possibility of getting approval in at least one country. Since the sponsor can’t choose the rapporteur countries like he can in other procedures, this also leaves him at a disadvantage.

Mutual Recognition Procedure

This procedure requires the drug to be already approved in a MS.

This procedure is based upon the principle that a marketing authorization and the evaluation in one Member State (the so-called reference Member State) ought to be recognized by the competent authorities of the other Member States (the so-called concerned Member States), that is, if a Member State concedes a national MA to a drug, other Member States can recognize the evaluation conducted by it and grant a MA for the drug themselves.

It’s also noteworthy to point out that both a Member State and the Sponsor can trigger the Mutual Recognition Procedure.

After the first marketing authorization in the Community is granted, the marketing authorization holder may request one or more Member State(s) to recognize an authorization approved by the reference Member State, by submitting an application in accordance with Article 28 of Directive 2001/83/EC.

Within 90 days of receipt of a valid application, the reference Member State will provide the assessment report together with the approved summary of product characteristics, labeling and package leaflet to the concerned Member States and to the marketing authorization holder.

Within 90 days of the receipt of these documents, the concerned Member States shall recognize the decision of the reference Member State and the approved summary of product characteristics, package leaflet and labeling by granting a MA.

If any country refuses to grant a MA by safety reasons, the matter will be taken to The Co-ordination Group for Mutual Recognition and Decentralized Procedures, which will attempt to make all member states reach a consensus in 60 days. If it fails, the request will be taken to the CHMP and treated like a centralized procedure.

Decentralized procedure

The decentralized procedure works in a similar way as the mutual recognition one, except here the medicinal product in question has not yet received a marketing authorization in any Member State at the time of application. Like the MRP, a reference member state is chosen, which will evaluate the MAA. The remaining member states then proceed to give their opinion on the evaluation. If all concerned member states agree on the evaluation by the reference member state, the drug will be approved and allowed for sale in those countries. If a member state disagrees, the Co-ordination Group for Mutual Recognition and Decentralized Procedures will, like in the MRP, play a referee role.

ADVANTAGES and DISADVANTAGES of MRP & Decentralized Procedure

Both the MRP and the decentralized procedure carry a set of advantages and disadvantages that sponsors ought to know before setting their product market strategy. Both of them allow a sponsor to avoid the need to go through different national procedures in each country. Moreover, they aren’t as risky as the centralized procedure, and, in the case of the MRP, the sponsor can choose the reference member state that will conduct the evaluation of the drug product (by first attaining a MA in that country). In both these procedures, fees have to be paid to all Member states who participate in the process, and, unlike the centralized procedure, the sponsor may have to attribute a different name for its drug product in different Member States., which may hurt brand awareness.

The MRP often sees disagreements between member states, holding up the procedure and causing delays. In these occasions, a lengthy dispute solving mechanism has to be employed, costing both time and money to the sponsor

The decentralized procedure avoids some of the potential disputes between member states by engaging each of the member states the applicant wishes to apply to at the time the first marketing authorization is made. Disputes are this less common in the decentralized procedure than in the MRP. Lastly, the decentralized procedure is faster than the MRP.  The first can take up to 210 days to complete its two steps. The MRP, on the other hand, a national MA is first needed, which can take up to 210 days, alongside the update period of the MA license before the MRP procedure starts proper, which can take more 180 days. The take home message is that there is no one-size fits all in regards to drug authorization procedures. Each one of the four available has different advantages and disadvantages, which have to be carefully weighed out by the sponsor.

Drug Approval Process for the US

http://www.jpsr.pharmainfo.in/Documents/Volumes/vol5issue06/jpsr05061302.pdf

Types of Applications Submitted to the US FDA for New Medicines/Treatments

Investigational New Drug (IND) – Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines.

New Drug Application (NDA) – When the sponsor of a new drug believes that enough evidence on the drug’s safety and effectiveness has been obtained to meet FDA’s   requirements for marketing approval, the sponsor submits a new drug application (NDA) to FDA. The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.

Biologic License Application (BLA) – Biological products are approved for marketing     under   the provisions of the Public Health Service Act. The Act requires a firm who manufactures a    biologic for sale in interstate commerce to hold a license for the product. A biologics license   application is a submission that contains specific information on the manufacturing processes,  chemistry, pharmacology, clinical pharmacology and the medical effects of the biologic product. If the information provided meets FDA requirements, the application is approved and a license is issued allowing the firm to market the product.

US Drug Approval Process

If an IND drug survives the clinical trials (phase 1-3), an NDA is submitted to the FDA. An NDA contains all the preclinical and clinical information obtained during the testing phase. The application contains information on the chemical makeup and manufacturing process, pharmacology and toxicity of the compound, human pharmacokinetics, results of the clinical trials, and proposed labeling. An NDA can include experience with the medication from outside the United States as well as external studies related to the drug.

After receiving an NDA, the FDA completes an independent review and makes its recommendations. The Prescription Drug User Fee Act of 1992 (PDUFA) was designed to help shorten the review time. This act allowed the agency to collect user fees from pharmaceutical companies as financial support to enhance the review process. The 1992 Prescription Drug User Fee Act (PDUFA) established a two-tiered system – Standard Review and Priority Review.

Standard Review is applied to a drug that offers at most, only minor improvement over existing marketed therapies. The 2002 amendments to PDUFA set a 10 month goal for a standard review.

Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where none existed. The goal for completing a Priority Review is six months.

If during the review the FDA staff feels there is a need for additional information or corrections, they will make a written request to the applicant. During the review process it is not unusual for the FDA to interact with the applicant staff.

The following four FDA programs are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening3 condition: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation.

Drug development in the fast lane: FDA approaches to expedited approval.

Fast track designation applies to the drug (either alone or in combination with other drugs) and the specific use for which it is being studied. The term drugrefers to the combination of two or more drugs if the combination is the subject of the fast track designation or request. Where appropriate, FDA may grant designation to the development of a new use of an approved drug.

1. Serious Condition
2. Demonstrating the Potential to Address Unmet Medical Need

The type of information needed to demonstrate the potential of a drug to address an unmet medical need will depend on the stage of drug development at which fast track designation is requested. Early in development, evidence of activity in a nonclinical model, a mechanistic rationale, or pharmacologic data could be used to demonstrate such potential. Later in development, available clinical data should demonstrate the potential to address an unmet medical need.

BREAKTHROUGH Therapy Designation

Section 506(a) of the FD&C Act provides for designation of a drug as a breakthrough therapy “. . . if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” It is important to recognize that the standard for breakthrough therapy designation is not the same as the standard for drug approval. The clinical evidence needed to support breakthrough designation is preliminary. In contrast, as is the case for all drugs, FDA will review the full data submitted to support approval of drugs designated as breakthrough therapies to determine whether the drugs are safe and effective for their intended use before they are approved for marketing.

ACCELERATED APPROVAL

The accelerated approval provisions of FDASIA in section 506(c) of the FD&C Act provide that FDA may grant accelerated approval to:

. . . a product for a serious or life-threatening disease or condition . . . upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

For drugs granted accelerated approval, post marketing confirmatory trials have been required to verify and describe the anticipated effect on IMM or other clinical benefit

Post marketing surveillance is important, because even the most well-designed phase 3 studies might not uncover every problem that could become apparent once a product is widely used. Furthermore, the new product might be more widely used by groups that might not have been well studied in the clinical trials, such as elderly patients. A crucial element in this process is that physicians report any untoward complications. The FDA has set up a medical reporting program called Medwatch to track serious adverse events (1-800-FDA-1088). The manufacturer must report adverse drug reactions at quarterly intervals for the first 3 years after approval, including a special report for any serious and unexpected adverse reactions

Regulatory Links for the US FDA Guidances

Guidance for Industry -Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

Good Review Practice: Refuse to File, available on the Internet at http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciesprocedures/ucm370948.htm and CBER SOPP 8404, Refusal to File Procedures for Biologic License Applications (August 27, 2007), available on the Internet athttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073474.htm.

Regulatory Links for the EU:

Directive 2001/20/EC of the European Parliament and of the Council of 4 April2001 on the approximation of the laws, regulations and administrative provisions of the MS relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. http://eur-lex.europa.eu/LexUriServ/LexUriServ.douri=OJ:L:2001:121:0034:0044:en:PDF

Detailed guidance on the request to the competent authorities for authorization of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01) http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2010:082:0001:0019:

EFPIA: Status of the implementation of the European Union Clinical Trials

Directive at member state level, Circular N° 12.784 , June 2008

Klingmann I et al. Impact on Clinical Research of European Legislation. Final report, February 2009http://www.efgcp.be/downloads/icrel_docs/Final_report_ICREL.pdf

Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC, Public Consultation Paper, ENTR/F/2/SF D(2009) 32674http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/clinicaltrials/docs/2009_ 10_09_public-consultation-paper.pdf

Report of the multidisciplinary workshop on “A single CTA in multinational clinical trials – dream or option?”, Brussels, Belgium, 7 July 2009http://www.efgcp.be/Conference_details.asp?id=265&L1=10&L2=2&TimeRef=2

Clinical Trials Facilitation Groups, Guidance document for a VoluntaryHarmonization Procedure (VHP) for the assessment of multinational Clinical Trial Applications, Version 2 ; Doc.ref.: CTFG/VHP/2010/Rev1, March 2010 http://www.hma.eu/uploads/media/VHP_version_2_March_2010.pdf

European Commission Enterprise Directorate-General. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use (ENTR/CT2), Revision 1, February 2006http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/12_ec_guideline_200 60216.pdf

The EFGCP Report on The Procedure for the Ethical Review of Protocols forClinical Research Projects in Europe, Update April 2010http://www.efgcp.be/EFGCPReports.asp?L1=5&L2=1

European Commission-European Medicines Agency Conference on the Operation of the Clinical Trials Directive (Directive 2001/20/EC) and Perspectives for the Future, Report on the Conference held on 3 October 2007 at the EMEA, London, Doc. ref.: EMEA/565466/2007http://www.eortc.be/services/doc/EUCTD/EC-EMEA_report_CT_20071003.pdf

Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC,Summary of responses to the public consultation paper, SANCO/C/8/SF/dn D(2010) 380240http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/clinicaltrials/2010_03_30_summary_responses.pdf

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to Medicinal Products for Human Use, as amendedhttp://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2001_83/dir_2001 _83_de.pdf

Responses to the Public consultation paper “Assessment of the functioning of the ‘Clinical Trials Directive’ 2001/20/EC”, March 2010http://ec.europa.eu/enterprise/sectors/pharmaceuticals/human-use/clinicaltrials/ developments/responses_2010-02_en.htm

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:

Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such products http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:091:0013:0019:

European Commission, Impact Assessment, 2010 Roadmaps “Legislative proposal on a Regulation/Directive amending the Clinical Trials Directive 2001/20/EC”, Version 2, 23/03/2010http://ec.europa.eu/governance/impact/planned_ia/docs/47_sanco_clinical_trials_directive_en.pdf

//////////Regulatory Approval Pathways,  EU vs US

Fraud and Major GMP Violations at API Manufacturers in India and China

 

Two Non-Compliance reports to API manufacturers from the Far East  published in the EudraGMDP database reveal once more that basic requirements laid down in the ICH Q7 Guideline are not implemented. Read more details about those Non-Compliance Reports.

http://www.gmp-compliance.org/enews_05225_Fraud-and-Major-GMP-Violations-at-API-Manufacturers-in-India-and-China_15165,15339,S-WKS_n.html

 

The Non-Compliance reports in the Eudra-GMDP database of the European Medicines Agency (EMA) are – to a certain extent – the European counterpart of FDA’s Warning Letters. These reports are first drawn up then put in the database after a GMP inspection performed by a representative of the European national competent authorities at an API or medicinal product manufacturer showed serious GMP deficiencies. Similar to Warning Letters, the consequences of Non-Compliance reports are for the companies concerned critical, e.g. withdrawal of the GMP certificate or product recalls.

Two Non-Compliance reports issued at the end of last year concerned API production sites in China and India.

Regarding the Chinese manufacturer “Minsheng Group Shaoxing Pharmaceutical Co. Ltd“, GMP inspectors from the French competent authority found 2 critical and 4 “major” deficiencies. Those deficiencies are summarised below:

• Falsification of source of starting materials: the starting materials supposed to have been manufactured in-house actually came from an external non GMP-compliant supplier and have been repackaged and relabelled accordingly (critical deficiency).
• The API manufactured according to the Chinese Pharmacopoeia was wrongly and intentionally released as USP quality; there was no traceability of the testing activities (critical deficiency).
• The cleaning and maintenance operations of the manufacturing line were insufficient (major).
• Deficient equipment design (pipelines); non-compliant transfer of the intermediate solution using nitrogen; non-compliant change management with regard to equipment (major).
• Hoses were lying on a dirty floor of an area not mentioned in the general layout of the site. Those hoses were unidentified and their cleaning status was unclear (major).
• Audit trail function in the chromatographic system was deactivated; there was no procedure in place for audit trail (major).

By the way, the inspection of the Chinese manufacturer performed by the French authority was part of the prequalification programme of the WHO which means that it had been initiated by the manufacturer himself within the framework of his application for the inclusion of his products in the list of prequalified pharmaceutical APIs of the WHO.

Secondly, the inspection of the Indian company “AstraZeneca Pharma India Ltd.” was carried our by inspectors of the Swedish competent authority. The GMP deviations observed are summarised below:

• The manufacturing process of the API was not sufficiently validated (major).
• The documentation routine was not GMP-compliant (major).
• Data integrity wasn’t assured (major).
• Design and maintenance of the equipment was insufficient (major).

The GMP deficiencies discovered in both production sites concern essential GMP requirements for the manufacture of APIs as laid down in the ICH Q7 Guideline and in the EG GMP Guide Part II since already 16 years. Unfortunately, GMP inspectors from European authorities, the EDQM and the FDA are – again and again – confronted to such GMP deficiencies, mainly in Indian and Chinese manufacturing sites.

 

///////// gmp Violations, API Manufacturers, India,  China

ECA publishes revised version of Good Practice Guide on Process Validation

 

After the FDA moved towards a life cycle approach with its Process Validation Guidance in 2011, the EU GMP Guide now followed with the revision of Annex 15, also moving to modern process aspects (e.g. life cycle approach). But how can the industry implement the new process validation requirements? The ECA’s Good Practice Guide on Validation does provide answers.

Since the publication of FDA´s Process Validation Guidance in 2011, validation has become a life cycle approach with focus on process knowledge and process understanding based on scientific sound principles. In addition, with the revision of Annex 15 of the EU GMP Guide, the EU has also been moving to modern process aspects (e.g. life cycle approach).

The question is how to implement these new requirements – in the USA and  in Europe?

To answer this question, an ECA Working Group has revised the Version 1 of ECA´s Good Practice Guide on Validation. With the revision the group wants to provide support to both regulators and industry. On one hand, the guide contains the main elements of the new approach (“what to do”). On the other hand, it also serves as a supporting guide for the implementation (“how to do”).

The revised version comprises 174 pages divided in 5 chapters and 5 annexes (with detailed analyses of the regulatory guidances).

The topics covered are e.g.:

• risk based qualification and validation
• legacy products
• statistics
• case study about process validation
• case study about continued/ongoing process verification in biopharmaceutical manufacturing

The ECA Good Practice Guide on Validation will be officially launched at ECA´s Annex 15 Conference on 25/26 November 2015 in Berlin. All participants will receive a free copy of the document.

http://www.gmp-compliance.org/enews_05089_ECA-publishes-revised-version-of-Good-Practice-Guide-on-Process-Validation_9379,15093,15290,15163,Z-VM_n.html

 

ECA´s Annex 15 Conference on 25/26 November 2015 in Berlin. All participants will receive a free copy of the document.

Course No 9379

Annex 15 Conference

25-26 November 2015, Berlin, Germany

Background

Since 2001 the Annex 15 has been state of the art for Validation Master Plan, Qualification, Validation, Cleaning Validation and Change Control within the EU. In the meantime ICH
Q 8-11 has been published. The FDA has implemented most of these ICH guidelines and introduced a Validation Process Life Cycle in its Process Validation Guidance from 2011. The EMA has published a revision of its Note for Guidance on Process Validation to implement this new aspects too. This is also the reason why the Annex 15 has to be revised. The first thoughts have been provided in a concept paper. In February 2014 was a draft published and now the final version of the revision is available.

Programme

ECA Annex 15 Survey
Industry view on Annex 15

Overview of the new Annex 15 revision view of an EU GMP Inspector
History of validation guidelines in the EU
The Annex 15 revision
The EMA Process Validation revision
What´s really new?

Organisation and Planning for Qualification and Validation
Integration of outsourced data in a validation
What is an “appropriate validation oversight” ?
New requirements in the Validation Master Plan
Requirements regarding the qualification of suppliers
Requirements regarding Risk Management

Validation Documentation
Good Documentation Practice – what does that mean for validation?
How to support knowledge management
Content of validation protocols and reports
Conditional approvals – a challenge

Qualification – Annex 15 revision vs FDA Process Validation Guidance
The new first step(s) URS/FDS
How to use FAT and SAT?
Combinations of qualification stages IOQ/OPQ
Interface PQ/Process Validation
Is the requirement to qualify utilities really new?
How to handle the qualification of established equipment (in-use) in the future?
What´s about alternatives (ASTM E 2500)?
Are there differences to the FDA Process Validation Guidance?

Process Validation in the new Annex 15 revision – in the light of modern
life cycle thinking
The Process Validation Life Cycle
Modern vs. traditional approach
What is a hybrid approach?
How is bracketing possible?
Are the three magic runs still applicable?
Clarification of the terms continuous process verification, continued process verification, ongoing process verification
Is the Annex 15 revision in line with the FDA Process Validation Guidance?

Cleaning validation in the new Annex 15 – how to implement the PDE concept?
Grouping of equipment – a new possibility?
How to validate manual cleaning operations`
The new acceptance criteria: PDE – how to implement?
Choice of worst case products taking account of toxicity PDE values and solubility
How to determine the cleaning validation batches?
Cleaning verification – what´s that?

Transport verification – solutions for future challenges
Requirements of Annex 15
Regulatory expectations
Qualification, Verification, Validation
Lean Verification Approach
Actual status, future challenges

Packaging Validation – from fill to finish
Requirements of Annex 15
Qualification of packaging lines
The validation of primary vs secondary packaging processes

 

 

BERLIN, GERMANY

 

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Drug Master File Procedures in the EU, the US and Japan 22-23 October 2015, Hamburg, Germany

Drug Master File Procedures in the EU, the US and Japanhttp://www.gmp-compliance.org/daten/seminarpdf/ECA_DMF_2015.pdf

22-23 October 2015, Hamburg, Germany

Speakers

Marieke van Dalen, Aspen Oss B.V, The Netherlands

Dr Hiltrud Horn, Horn Pharmaceutical Consulting, Germany

Dr Usfeya A Muazzam, Bonn, Germany
Dr Boris Pimentel, DSM-Nutritional Products AG, Switzerland
Dr Wilhelm Schlumbohm, Berlin, Germany

Learning Objectives

This education course is intended to provide guidance on the procedures for the European ASMF, the US-DMF and the Japanese DMF. You will get to know
how to describe manufacturing processes
how to compile data for drug substance stability, impurities and residual solvents
which are the important points to consider for US-DMFs
which are the requirements for Japanese DMFs
how to handle changes in European, US and Japanese DMFs

Participants will have the opportunity to take part in one of two parallel workshops about
Description of the manufacturing process or How to compile data for Impurities and Residual Solvents

Background

Documentation of the drug substance quality is an integral part of any marketing authorisation application. In Europe the most common document for this purpose is the Active Substance Master File (ASMF) as long as the applicant has no Certificate of Suitability of the pharmacopoeial monograph (CEP). The European ASMF procedure differs significantly from the US-DMF procedure and for strategic reasons it is very important to take these differences into account. Moreover there are particular requirements for DMFs in Japan. For global acting companies it is a big challenge to handle the different procedures of compiling, submitting, changing and maintaining Drug Master Files in an efficient way.

Target Group

The education course is designed for all persons involved in the compilation of pharmaceutical dossiers for marketing authorisations especially for Drug Master Files who want to become familiar with the different DMF procedures. Furthermore, the course will be of interest to personnel from Quality Units of the pharmaceutical and the API industry.

Programme

The European Active Substance Master File procedure – An Introduction
Chemical pharmaceutical documentation for active substance(s) –
Regulatory requirements in EU, USA
Types of active substances – types of documentation
CTD Module 3, CEP and ASMF (former DMF)
CEP for a substance for TSE risk assessment

Drug Master File Procedures in the US
Types of Drug Master Files
Submissions to DMFs
Closure of a DMF
US vs EU DMF – differences in the procedure

How to document drug substance stability
Stability Guidelines
Stability Testing of new drug substances and drug products
Storage Conditions
Bracketing and Matrixing Designs
Stability data from new drug dosage forms
How to document evaluation of stability data
Optimising the submission

Residual solvents and Impurities: synthesis derived Impurities, Metals and genotoxic Impurities
Guidelines
Impact of the new guidelines ICH Q3D and ICH M7
Sources of Impurities
Setting and justification of specifications
Residual solvents, solvent classes
Content and scope of data – documentation requirements
Frequent mistakes

Handling Changes in European Drug Master Files
Why is there a need for changes
Types of changes
How to communicate with the customers and how to get feed back
Differences between ASMF and CEP
How to maintain an ASMF
Keeping track of the customers’ stand in relation to a specific change

Handling Changes in US Drug Master Files
Post approval activities
Reporting requirements to the FDA (CBE 0, CBE 30, Annual Report)
Post approval commitments and post approval reporting requirements
Risk evaluation and mitigation strategies (REMS)
Major re-organisation of a US-DMF
Holder obligations

Requirements of the Drug Master File Procedure in Japan
Regulatory procedures in Japan
points to consider when dealing with Japanese authorities
Regulatory documentation standards
Master File registration procedure
Master File review by Japanese authority

Changes and Maintenance of Japanese Drug Master Files
Change procedures and communication with the Japanese authority
Types of changes
Notification of changes

Costs:
Non-ECA Members: EUR 1.790,–
ECA Members: EUR 1.590,–
EU GMP Inspectorates: EUR 895,–
APIC Members (does not include ECA membership): EUR 1.690,–
(All prices excl. VAT)

If you have any questions, please contact us:

Tel.: +49 (0)6221 / 84 44 0 E-Mail: info@concept-heidelberg.de

http://www.gmp-compliance.org/eseminar_9255_Drug-Master-File-Procedures-in-the-EU–the-US-and-Japan_9255_n.html

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EU: New GMP Implementing Act published

The EU Commission has published a new public consultation on an Implementing Act on GMP principles and guidelines for medicinal products for human use.

The EU Commission has published a new public consultation on an Implementing Act on Principles and guidelines on good manufacturing practices for medicinal products for human use.

http://www.gmp-compliance.org/enews_05017_EU-New-GMP-Implementing-Act-published_9304,9232,10335,Z-QAMPP_n.html

The reason is that once Regulation (EU) No 536/2014 on clinical trials becomes applicable, manufacture and import of Investigational Medicinal Products (IMPs) for the use in clinical trials carried out under that Regulation cannot follow GMP for IMPs set out in Directive 2003/94/EC. They then have to be manufactured or imported under regulations laid down by the Delegated Act or other specified regulation. It is therefore necessary that Directive 2003/94/EC is revised by a new Implementing Directive on principles and guidelines of good manufacturing practice for medicinal products for human use (without IMPs).

The EU Commission states that because “good manufacturing practice for medicinal products for human use already exists and is generally well-functioning, there is no need to reinvent the wheel”. So the GMP related consultation documents carry over elements set out in Directive 2003/94/EC relating to medicinal products for human use.  GMPs for advanced therapy medicinal products will be introduced with a new provision.