WHO issues revised Guideline on HVAC Systems

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems for the manufacture of non-sterile forms. As most guidelines on this topic address the requirements for sterile dosage forms, the previous version was gladly accepted by industry. Learn more about the revised guideline on HVAC systems.


The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems used for the manufacture of non-sterile dosage forms. As most guidelines on this topic address the requirements for sterile forms, the previous version (TRS 961, Annex 1) from 2011 was gladly accepted by industry. Mentioned are non-sterile dosage forms as tablets, capsules, liquids or ointments, but also for the final steps in the manufacture of APIs. The WHO guideline means to provide guidance specifically for the areas design, installation, qualification and maintenance of ventilation systems. For the manufacture of highly potent materials the WHO refers to their Guideline TRS 961, Annex 3.

The biggest changes comprise:

  • The chapter “Premises” was moved to the front to emphasize its importance. The chapter now further comprises some sample layouts
  • The section “Commissioning, Qualification and Validation” was revised to match it with the  WHO Guideline TRS 937, Annex 4 (Supplementary guidelines on good manufacturing practices: validation)
  • The part “Maintenance” was removed from the part “Commissioning, Qualification and Validation” and is now a separte chapter
  • In addition a number of comments were added, graphs revised, and the overall readability was improved

Due to the many references and the numerous and improved illustrations the document is a good source for the (exemplary) requirements in the manufacture of solid and non-sterile dosage forms.

To find out more please visit the WHO website where you will find the draft document SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS. The deadline for comments is the 12 July 2016. The results are expected to be discussed during the 51st WHO expert committee meeting in October.

///////////WHO,  revised Guideline,  HVAC Systems


EU GMP Annex 1 Revision 2016 – what does the pharmaceutical industry expect?

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech at the Pharma Congress 2016 about the revision of Annex 1 of the EU GMP Guide. Read here what the pharmaceutical industry expects form the new Annex 1.


Europe’s biggest Pharma Congress of its kind took place in Düsseldorf on 12 and 13 April. With more than 1000 participants, 90 exhibitors and 10 GMP conferences this Congress 2016 has been the biggest since the first one 18 years ago. 50 lectures, almost exclusively case studies from pharmacuetical companies such as Pfizer, Novartis, Boehringer Ingelheim and many more were discussed. Special attention was paid to the keynotes at the beginning of each congress day.

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech about the revision of Annex 1 of the EU Guidelines to Good Manufacturing Practice. The first version dates already back to the year 1972. Dr Haefele stated that there had already been five revisions since this time but no fundamental review. This means the time has come to revise this fundamental document on the regulation of sterile manufacture in Europe.

Dr Haefele demonstrated the need for action on one hand by a comparison with the FDA Aseptic Guide and on the other hand by means of his own commenting. Friedrich Haefele said that priority should be given to harmonisation. He basically believes that Annex 1 should remain reserved for sterile parenteral products and that other sterile products or active pharmaceutical ingredients should be regulated in other documents or in specific annexes. He also wants a separation between aseptically manufactured and terminally sterilised products in the new Annex 1.

He considers DIN ISO 14644-1 to be a central document that is used for the classification of clean rooms in the European Guideline but also in the US Guide. Dr Haefele is not bothered by the fact that the limit for 5 µm particles has been deleted from the grade ISO 5 (ISO 4.8). According to him it should also be deleted from the European requirements. Deviations in the case of 0.5 and 5 µm particles occur essentially in parallel so that it should be possible to renounce to the limit for 5 µm particles.

Dr Haefele also proposed a simplification for the microbiological environmental monitoring. Settle plates as well as microbial air sampling are required in Europe at the moment. According to Dr Haefele only the microbial air sampling should be compulsory whereas the use of settle plates should be optional or additional. The use of average values in the microbiological monitoring in the clean room should be dismissed. With the use of isolators with validated decontamination cycles the microbiological monitoring could be reduced to the essential pursuant to ICH Q9 Quality Risk Management.

In contrast to the FDA Aseptic Guide the European Annex 1 contains requirements concerning the crimping process as well as a differentiation between aseptic and clean processes. For the latter Dr Haefele wants a clear definition of “Grade A Air Supply” that should be used for protection during the process according to Annex 1. Dr Haefele stated that the industry has its opinion concerning this but that it should also be recorded in the relevant official document. By this he meant the use of air filtered according to the requirements of grade A without considering the microbiological requirements.

There are important differences between Annex 1 and the Aseptic Guide in the area of sterilisation. The US document contains no indications for a terminal product sterilisation. It is contained in the EU document. Dr Haefele proposes to limit the requirement for a sterilisation with pure steam primariliy to the terminal product sterilisation and to also allow other methods e.g. sterilisation with ethylene oxide for example for so-called ready-to-use materials.

He sees further potential for improvement concerning the topic sterile filtration. He considers that the integrity testing after sterilisation immediately before filling can be omitted since the data of the filter validation and the integrity testing after filling give adequate security. To renounce to the obligatory integrity testing after sterilisation and before use, reduces the complexity of the aseptic set-up and when constructing facilities.

A further difference concerns the quality oversight. In Europe there is no requirement that the quality assurance (physically) must take place on-site during aseptic processes. But the Aseptic Guide requires a QC oversight and here, especially the media fill is mentioned. Dr Haefele invoked a harmonisation of the requirements, in order to strengthen the European philosophy, however. Quality assurance is a system and not an organisation. Mr. Haefele proposed a further change concerning the media fill in isolators. Here, interventions are carried out from the outside when carrying gloves. This means that they are “person-neutral”. The requirement that the qualification of interventions during the media fill has to be done person-specific should therefore be omitted for media fills in isolators.

As concerns the topic disinfection Mr. Haefele would prefer the admission of hydrogen peroxide for the decontamination of surfaces in isolators and material locks as well as the dispensation with the mandatory rotation when using disinfectants.
A further topic in Annex 1 is the monitoring of the integrity of containers containing sterile medicinal products. At the moment, the Annex requires a 100% integrity testing only for containers closed by fusion (glass ampoules and BFS containers). Dr Haefele would prefer more openness up to suitable controls for all packaging systems or pharmaceutical dosage forms.

Finally, he reaffirmed the use of modern barrier techniques for the aseptic manufacture as state-of-the-art and repeated his wish for a harmonisation of the requirements for sterile and aseptically produced medicinal products. MRA, mutual recognition agreements, could reduce the number of regulatory inspections at the companies.

Currently, the publication of the draft of the new EU GMP Annex 1 is planned for autumn 2016.

Source: Pharma Kongress 2016 (companies who wish to book a booth in 2017 can register here)
/////Dr Friedrich Haefele, Vice President, Fill & Finish Biopharma,  Boehringer Ingelheim, EU GMP Annex 1 Revision 2016,  pharmaceutical industry,

FDA approved a switchover from batch to the new technology for production of HIV drug Prezista, Darunavir on a line at its plant in Gurabo, Puerto Rico

New Drug Approvals

Above is an Illustration example,

FDA urges companies to get on board with continuous manufacturing

The FDA gave Johnson & Johnson’s ($JNJ) Janssen drug unit the thumbs up last week for the continuous manufacturing process that it has been working on for 5 years. The agency approved a switchover from batch to the new technology for production of HIV drug Prezista on a line at its plant in Gurabo, Puerto Rico……http://www.fiercepharma.com/manufacturing/fda-urges-companies-to-get-on-board-continuous-manufacturing

Darunavir structure.svg
Darunavir ball-and-stick animation.gif


Just after opening a refurbished manufacturing facility in Cape Town, South Africa earlier this year, pharma giant Johnson & Johnson ($JNJ) recently opened the doors to its Global Public Health Africa Operations office there.

The company has invested $21 million (300 million rand) in the facilities. The global public health facility will focus on HIV, tuberculosis and maternal, newborn and child health, South Africa – The Good News reported.

“This (investment) tells us that South…

View original post 224 more words

FDA´s new policy regarding grouping of supplements for CMC changes

The US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes. Find out more about Policy and Procedures regarding the Review of Grouped Product Quality Supplements.


On April 19, 2016 the US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes to multiple approved new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biological license applications (BLAs) submitted by the same applicant.

The agency says the goal of its new policy is to make the process more efficient and consistent when reviewing grouped supplements.The term “grouped supplements” is used to describe two or more supplements reviewed and processed using the procedures set forth in the new document, though FDA makes clear that supplements cannot be grouped if submitted by a different applicant or if the supplements provide for different CMC changes. “The supporting data necessary for the review of the CMC changes should be the same for each of the grouped supplements,” FDA says. “Any supplement that provides for the same CMC changes but necessitates the review of data that is unique to that supplement (e.g., product-specific data) should not be grouped.”

Supplements can be grouped when the following criteria are met:

  • The cover letter for the supplements clearly states the purpose of the proposed CMC changes and indicates that the supplement is one of multiple submissions for the same change.
  • Each supplement includes a list of the application numbers (NDA, BLA, and ANDA, as appropriate) and identifies the drug products that will be covered by the CMC changes.
  • The supplements have the same submission date on Form FDA 356h.

“On a case-by-case basis, the Center may also group supplements that do not meet some or any of the criteria described above, if grouping the supplements is advantageous to the review process,” FDA says.

Circumstances where this may occur include cases when an applicant submits a group of supplements for the same CMC change and then, at a later date, submits additional supplements for the same change and requests FDA officials to include the second set of supplements in the group.

The Regulatory Business Project Manager (RBPM) and Branch Chief (BC) of the relevant review division will decide on a case-by-case basis whether such changes will be allowed, though FDA notes that “consideration will be given to whether the goal date for the original group of supplements could still be met if the second set of supplements is added to the review.”

Additionally, seven new procedures were outlined by FDA in the MAPP (Manual of Policies and Procedures).

Source: Regulatory Affairs Proffessional Society – See more at:  OFFICE OF PHARMACEUTICAL QUALITY Review of Grouped Product Quality Supplements

//////// supplements, FDA, MAPP, supplements for CMC changes

EMA publishes Q A on data required for sterilized primary packaging materials used in aseptic manufacturing processes

The European Medicines Agency, EMA, recently published questions and answers on what data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process. Read more about “What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?“.


The European Medicines Agency, EMA, recently published questions and answers on quality of packaging materials (H+V April 2016):

“3. What data is required for sterilisation processes of primary packaging materials subsequently used in an aseptic manufacturing process?
Terminal sterilisation of the primary packaging, used subsequently during aseptic processing of the finished product, is a critical process and the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product. Both need to be assured for compliance with relevant Pharmacopoeial requirements for the finished product and product approval.

The site where sterilisation of the packaging materials takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity1. When GMP certification is not available, certification that the sterilisation has been conducted and validated in accordance with the following ISO standards would be considered to provide an acceptable level of sterility assurance for the empty primary container:

  • I.S. EN ISO 20857:2013 Sterilization of Health Care Products – dry Heat – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 20857:2010);
  • I.S. EN ISO 11135:2014 Sterilization of Health-care Products – Ethylene Oxide – Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11135:2014);
  • I.S. EN ISO 17665-1:2006 Sterilization of Health Care Products – Moist Heat – Part 1: Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS 17665-2:2009 Sterilization of health care products — Moist heat — Part 2: Guidance on the application of ISO 17665-1;
  • I.S. EN ISO 11137-1:2015 Sterilization of Health Care Products – Radiation – Part 1: Requirements for Development, Validation and Routine Control of a Sterilization Process for Medical Devices (ISO 11137-1:2006, Including 1:2013);
  • I.S. EN ISO 11137-2:2015 Sterilization of Health Care Products – Radiation – Part 2: Establishing the Sterilization Dose (ISO 11137-2:2013);
  • I.S. EN ISO 11137-3:2006 Sterilization of Health Care Products – Radiation – Part 3: Guidance on Dosimetric Aspects.

It is the responsibility of the user of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of packaging materials. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This should be checked during inspections. The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

Dossier requirements:

The following details regarding the sterilisation of the packaging components should be included in the dossier:

1. The sterilisation method and sterilisation cycle;
2. Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;
3. The name and address of the site of sterilisation and, where available details of GMP certification of the site. Where the component is a CE-marked Class Is sterile device (e.g. sterile syringe), confirmation from the manufacturer that the component is a Class Is sterile device, together with a copy of the declaration of conformity from the Notified Body will suffice.

In the absence of GMP certification or confirmation that the component is a CE-marked Class Is medical device, certification that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.
1Sites located in the EU which perform sterilisation of primary packaging components only are not required to hold a Manufacturer’s/Importer’s Authorisation (MIA). Sites located in the EU, which carry out sterilisation of medicinal products, are required to hold a MIA in relation to these activities.”

Source: European Medicines Agency – Quality of medicines Q&A: Part 2 – Packaging.

///////////EMA,  Q&A, data, sterilized primary packaging materials,  aseptic manufacturing processes



Although relatively quiet in terms of any specific regulatory activities, the last 6 months have seen a plethora of publications that are associated with the ICH M7 guideline. Prominent within these was the Special Edition of Organic Process Research & Development in November 2015. This special edition focused on mutagenic impurities, examining the challenges and also opportunities faced when seeking to implement ICH M7.(5) This was timely as it aligned with the effective date for ICH M7 of January 2016; the guideline when finalized in June 2014 having a defined implementation phase of 18 months. ICH M7 is, in general, a well-written guideline that provides a flexible and pragmatic framework by which the risk posed by mutagenic impurities can be effectively managed. The flexibility provided by the guideline and the opportunities this presents in terms of science and risk based thinking are examined in depth through a series of articles within the special edition.
A tabulated summary of the special edition is described in Table 1.

Table 1

subject highlights authors
Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses? A survey of over 300 synthetic publications in OPR&D over a 10 year period clearly demonstrated that the synthesis of synthetic APIs was untenable without the use reactive, potentially mutagenic reagents/intermediates. That the principle of avoidance was fundamentally flawed Elder, D. P.; Teasdale, A.(6)
Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products The paper outlines a strategy for the systematic assessment of the risk posed by mutagenic degradants, describing how this relates to stress testing and long-term stability studies. Within this it seeks to define appropriate thresholds for identification directly related to the extent of degradation Kleinman, M. H.; Teasdale, A.; Baertschi, S. W. et al.(7)
Assessing the Risk of Potential Genotoxic Degradation Products in a Small Molecule Kinase Inhibitor Drug Substance and Drug Product The degradation profile resulting from stress testing of galunisertib is described, focusing on formation of two N-oxides, examining the site of oxidation and the relevance of the pathway under typical storage conditions. Strege, M. A.; Osborne, L. M.; Hetrick, E. M. et al.(8)
Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions Provides a comprehensive review of the existing evidence relating to sulfonate esters, examining the comprehensive mechanistic and kinetic studies and safety data. It also examines the current regulatory approaches and how this appears misaligned with the data. Snodin, D.; Teasdale, A.(9)
Mutagenic Impurities: Precompetitive Collaborative and Data Sharing Initiatives Examines the nature, impact, and successes of a series of cross industry initiatives covering areas such as structural evaluation (Q)SAR, data sharing–aromatic amines, boronic acids, purging and degradation. Elder, D. P.; Williams, R.; Harvey et al.(10)
Do Carboxylic/Sulfonic Acid Halides Really Present a Mutagenic and Carcinogenic Risk As Impurities in Final Drug Products? Examines evidence that indicates that in the case of both sulfonyl and acyl chlorides that Ames positive results relate to generation of a reactive species, halodimethyl sulphides (HDMSs) through reaction with DMSO and that this is the root cause of a positive response. Confirmatory negative data from other test solvents is also provided Amberg, A.; Harvey, J.; Spirkl, H.-P. et al.(11)
Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity The primary purpose is to raise awareness of the potentially mutagenic nature of boronic acids and stimulate further discussion/research in the areas. It provides mutagenicity data for some 40+ examples, examining the current status of in silico predictions and postulates a potential mechanism related to oxidation of boronic acids to yield oxygen radicals Hansen, M. H.; Jolly, R. A.; Linder, R. J.(12)
A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors Details an experimental approach that utilizes kinetic analysis to facilitate assignment of reactivity purge values. Betori, R. C.; Kallemeyn, J. M.; Welch, D. S.(13)
A Generic Industry Approach to Demonstrate Efficient Purification of Potential Mutagenic Impurities (PMIs) in the Synthesis of Drug Substances Based on vortioxetine and its associated PMIs predicted purge values based on the system described by Teasdale et al.(15) are compared with experimental values. The results show good correlation concluding that theoretical purge values can be used to predict purging of PMIs. Lapanja N, Zupanĉiĉ B, Toplak Ĉasar R et al(14)
Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates versus Measured Amounts The purging of MIs associated with the synthesis of MK-8876 were assessed using the approach described by Teasdale et al.(15)These predicted values were compared to measured values and shown to be conservative in comparison to experimental data. McLaughlin, M.; Dermenijan, R. K.; Jin, Y. et al.(16)
Several papers focused on control options, specifically ICH option 4, involving evaluation of the impact of process conditions upon the purging of mutagenic impurities. This concept was first described by Teasdale et al. in 2010(17) and augmented by a cross-industry evaluation published in 2013.(15) The practical use of such tools is examined through two papers, that of Nevenka et al.(14) and McLaughlin et al.(16) This is augmented by a further publication by Welch et al.(13)that describes work now being undertaken by an industry consortium to develop this tool still further as a robust in silico tool (Mirabilis). Welch et al. describe the work being undertaken to fully evaluate the potential fate of MIs under a range of common chemical transformations. A critical finding of these studies, examined through the reaction of benzyl bromide with triethylamine, was alignment between the rate constants and half-lives of the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol (Figure 2). This established the proof of concept that the kinetic information obtained from the stand-alone reaction can be used to predict impurity conversion in a more complex reaction.


Figure 2. Alignment between the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol.

Another area addressed in the special edition is that of sulfonate esters. This relates to the use of a sulfonic acid, used to form an API salt and the potential formation of sulfonate esters through reaction with alcoholic solvents. Snodin and Teasdale(9) have reviewed the available literature information concluding that the extensive evidence supports the view that such concerns are grossly exaggerated. In parallel to this publication there have been a series of correspondences involving the EMA quality working party, the following points were released following discussion at the CVMP committee.(18)

“The Committee endorsed the QWP response to the EDQM request for an opinion on new information on alkyl sulfonates. The QWP reviewed the article from Snodin et al. QWP acknowledges the scientific rationale in this article and that the formation of alkyl sulfonates is very low and very much depends on the reaction conditions. This makes the presence of these mutagenic impurities at toxicologically significant levels unlikely. However, as the presence and formation of these alkyl sulfonates cannot be totally excluded, QWP proposes the following approach: marketing authorization holders should justify via Risk Assessment that alkyl sulfonates are not expected to be present for their product, which may be sufficient.”

Of concern within this text is the comment that the presence and formation cannot be totally excluded; this is despite the evidence pointing clearly to fact that it can.




  1. 3.Analysis of Oligonucleotides and their related substances; Okafo, G., Elder, D., and Webb, M., Eds.; Chapter 2, pp 2228; ChromSoc Separation Sciences Series ISBN 9781906799144.

  2. 5.ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf (June 23, 2014).

  3. 6.Elder, D. E.; Teasdale, A. Org. Process Res. Dev. 2015, 19, 14371446, DOI: 10.1021/op500346q

  4. 7.Kleinman, M. H.; Teasdale, A; Baertschi, S. W. Org. Process Res. Dev. 2015, 19, 14471457, DOI: 10.1021/acs.oprd.5b00091

  5. 8.Strege, M. A.; Osborne, L. M.; Hetrick, E. M. Org. Process Res. Dev. 2015, 19, 14581464, DOI: 10.1021/acs.oprd.5b00112

  6. 9.Snodin, D; Teasdale, A. Org. Process Res. Dev. 2015, 19, 14651485, DOI: 10.1021/op500397h

  7. 10.Elder, D. P.; Williams, R; Harvey Org. Process Res. Dev. 2015, 19, 14861494, DOI: 10.1021/acs.oprd.5b00128

  8. 11.Amberg, A.; Harvey, J.; Spirkl, H.-P. Org. Process Res. Dev. 2015, 19, 14951506, DOI: 10.1021/acs.oprd.5b00106

  9. 12.Hansen, M. H.; Jolly, R. A.; Linder, R. J. Org. Process Res. Dev. 2015, 19, 15071516, DOI: 10.1021/acs.oprd.5b00150

  10. 13.Betori, R. C.; Kallemeyn, J. M.; Welch, D. S. Org. Process Res. Dev. 2015, 19, 15171523, DOI: 10.1021/acs.oprd.5b00257

  11. 14.Lapanja, N.; Zupanĉiĉ, B.; Toplak Ĉasar, R. Org. Process Res. Dev. 2015, 19, 15241530, DOI: 10.1021/acs.oprd.5b00061

  12. 15.Teasdale, A.; Elder, D.; Chang, S.-J. Org. Process Res. Dev. 2013, 17, 221230, DOI: 10.1021/op300268u

  13. 16.McLaughlin, M.; Dermenjian, R. K.; Jin, Y. Org. Process Res. Dev. 2015, 19, 15311535, DOI: 10.1021/acs.oprd.5b00263

  14. 17.Teasdale, A.; Fenner, S.; Ray, A Org. Process Res. Dev. 2010, 14, 943945, DOI: 10.1021/op100071n

  15. 21.Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (July 28, 2014).

  16. 24.Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products,http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM448638.pdf?_sm_au_=iNH61FD2WjHZP02F (May 2015).


ICH Q3D Implementation Working Group (IWG)—Training Modules

ICH Q3D Implementation Working Group (IWG)—Training Modules

ICH Q3D is a complex guideline. The overall requirement in terms of control is clear—there are defined limits for some 24 elements, and levels of the elements described must be controlled within these limits in the final drug product. Simple. The complexity comes when defining how this is achieved. The guideline provides a series of options to evaluate risk and effect control, ranging from control in each individual component based on a fixed dose for the product of 10 g (Option 1) to simply testing the final product (Option 3). A detailed description of the options and when/how these are applied as part of a risk assessment is beyond the scope of this review; the point is that there are significant challenges in applying the guideline practically solely using the guideline for that purpose. This was recognized by the ICH Expert Working Group responsible for the guideline, resulting in the establishment immediately after step 4 of an Implementation Working Group. A key objective of the IWG was to develop training materials to assist implementation.
In February ICH finally published the long awaited training modules.(2) These modules, produced by the ICH Q3D implementation working group, cover both safety and quality aspects, the areas covered are listed below:

Module 0

This provides an overview of the modules. Included within this is a very useful flow diagram,Figure 1, highlighting the anticipated overall process from the risk assessment through to definition of control strategy.

Modules 1–3 Cover Toxicology Aspects

Module 1—Different Routes of Administration

Module 2—Justification of Levels Greater than Permissible Daily Exposure Limits

Module 3—Non ICH Elements

Modules 4–7 Cover Chemistry (Quality) Aspects

Module 4—Large Volume Parenterals

Module 5—Risk Assessment

Module 6—Control

Module 7—Calculation Options

Highlighting some key points, module 5, relating to risk assessments, discusses the key role of GMP in assessing risk—this is an important and a helpful point relating to API manufacture. It emphasizes the importance of:


Design and qualification;


Maintenance procedures.

However, it also focuses on the risk arising from manufacturing equipment, making a relatively generic statement over the often more chemically aggressive nature of API manufacturing procedures compared to drug product manufacturing. It even suggests monitoring the drug substance for potential impurities arising from manufacturing equipment (e.g., stainless steel—Cr, Mn, Mo, V, Ni). It is a pity that this risk is highlighted without also making the point that it would be expected that such risk would be addressed as part of GMP and form part of the process accommodation procedure rather than rely on screening to verify.

Rightly the module makes the point that a significant potential source of elemental impurities arises from the use of metal catalysts in the synthesis of drug substances, especially if used in the latter stages of synthesis. It also states that:

“Knowledge of potential elemental impurities in synthetic steps prior to the final drug substance may provide information that can assist in the preparation of the risk assessment.”

This is an interesting point and one that cuts to the heart of the uncertainties around practical implementation. While a valid point, it raises key questions such as how many steps prior to the API should be assessed? Clearly this will be process/product specific, but it is a very real question any risk assessment will have to tackle.
Another interesting point made in the module is the potential for “platform” risk assessments. This is the concept of a risk assessment applicable across a series of products. One such platform may be for example, oligonucleotides.(3) In such instances, where the manufacturing process in terms of reagent type, equipment, and process conditions are similar irrespective of the precise end product, it should be possible to conduct an assessment based on one process and for this to relevant/transposable to comparable processes.


Figure 1
Module 6—Control of Elemental Impurities—also provides useful advice emphasizing the importance of control across the product lifecycle. In the context of the manufacture of the API, this requires oversight and governance over changes to the process that may affect the risk assessment, e.g., change in catalyst load, and so forth. Such changes require a re-evaluation and possibly confirmatory testing. Another point emphasized in the module is that routine testing of Class 1 metals, i.e., arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb), is NOT required unless there is an identified risk. This is a very important and helpful point clearly reiterating the core principle of ICH Q3D that any control strategy should be based on the risk assessment. This is especially important as several regulatory queries have been reported asking for data for Class 1 and also Class 2A metals for APIs.

One area described in Module 6 is the concept of periodic testing. This is an area of potential concern and ambiguity. It states that:

“Where the risk assessment indicates that routine testing is considered unnecessary but some additional assurance is needed post approval, periodic testing of the drug product or one or more individual components may be proposed by the applicant and implemented upon acceptance by the regional regulatory authority.”

An example is provided relating to use of a Pt catalyst in the manufacture of the API, this being the final step used in the API synthesis. In the example detectable levels of Pt at ∼ 20% of the PDE are observed (below the 30% limit stated in ICH Q3D), based on this periodic testing being proposed. In the case study described this may seem sensible but how close to reality is such an example? In such a case would an applicant simply not specify Pt on the API specification? The worry is that the option for periodic testing may be blunt instrument and be something that is regularly requested.

USP Chapter ⟨232⟩

USP very recently announced(4) a series of revisions to USP Chapter ⟨232⟩, Elemental Impurities, the revisions made being intended to align the general chapter more closely to ICH Q3D. One of the most significant is the removal of the need to routinely screen for Class 1 metals as part of any analysis, the final sentence in the text outlined below being deleted.

If, by process monitoring and supply chain control, manufacturers can demonstrate compliance, then further testing may not be needed. When testing is done to demonstrate compliance, proceed as directed in Elemental Impurities—Procedures ⟨233⟩.

This is a welcome and important amendment; the previous requirement making little scientific sense, there being no actual evidence that Class 1 metals would be more prevalent, for example, where a platinum catalyst was used than in the absence of a catalyst. Such catalysts are not a source of class 1 metals.


Overall there are likely to be challenges/uncertainties associated with ICH Q3D leading up to and for some period after the effective date as the guideline beds in, but the crucial fact is that all of the evidence to date indicates it is unlikely that there will be a widespread impact caused by issues of excessive levels of any elemental impurity whereby effective control cannot be realized.
/////////ICH Q3D, Elemental Impurities, Procedures ⟨233⟩, Training Modules

ICH M8 “Specification for Submission Formats for eCTD”

This additional specification describes the way files should be constructed for inclusion in the eCTD.

Key Points:

  • It is not necessary to use a product from Adobe or from any specific company to produce PDF documents.
  • All ICH regional regulatory authorities are able to read and accept PDF files saved as PDF version 1.4 through 1.7, PDF/A-1, or PDF/A-2 compliant to ISO 32000-1:2008.
  • The size of a PDF file should not exceed 500MB.

  • Regulatory authorities cannot guarantee the availability of any fonts except Times New Roman, Arial, and Courier and fonts supported in the Acrobat product set itself. Therefore, all additional fonts used in the PDF files should be embedded to ensure that those fonts would always be available to the reviewer.
  • Times New Roman, 12-point font, is adequate in size for narrative text and should be used whenever possible. Times New Roman font sizes 9-10 or an equivalent size of other recommended fonts are considered acceptable in tables but smaller font sizes should be avoided.
  • The use of a black font color is recommended. Blue can be used for hypertext links. Light colors can be difficult to read on a monitor as well as when printed, and should be avoided. The use of background shadowing can be difficult to read and should be avoided.
  • Pages should be properly oriented so that all portrait pages are presented in portrait and all landscape pages are presented in landscape.
  • A sufficient margin of at least 2.0 cm on the left side of each page for portrait and top of the page for landscape should be provided to avoid obscuring information. The remaining margins should be a Page 6 of 9minimum of 0.8 cm. Header and footer information can appear within these margins but should not appear so close to the page edge to risk being lost upon printing.
  • All pages of a document should include a unique header or footer that briefly identifies its subject matter.
  • Scanning should be avoided where possible.
  • It is recommended that scanning be undertaken at a resolution of 300 dots per inch (dpi) to balance legibility and file size. The use of grayscale or color is discouraged because of file size. After scanning, resampling to a lower resolution should be avoided.
  • Paper documents containing hand-written notes should be scanned at a resolution of at least 300 dpi. Hand-written notes should be done in black ink for clarity, 600 dpi is recommended. High-pressure liquid chromatography or similar images should be scanned at a resolution of at least 300 dpi.

  • Applicants should validate the quality of the renditions.
  • Hypertext links can be designated by rectangles using thin lines or by blue text as appropriate. Bookmarks are expected even if there is no TOC In the document. The use of no more than 4 levels in the hierarchy is recommended, but additional levels could be created for study reports if such bookmarks contribute to efficient navigation.
  • Relative paths should be used when creating hypertext links to minimize the loss of hyperlink functionality when folders are moved between disk drives.

  • The bookmarks should be collapsed when document is opened so that all bookmarks are at the first level.
  • The first page of the document should be numbered page 1, and all subsequent pages (including appendices and attachments) should be numbered consecutively with Arabic numerals. Roman numerals should not be used to number page. The only exception should be where a document is split because of its size, the second or subsequent file should be numbered consecutively to that of the first or preceding file.
  • Security fields should be set to allow printing, changes to the document, selecting text and graphics, and adding or changing notes and form fields. The exception to this rule includes regulatory forms with pre-existing security and literature references that need to be copyright protected.


Click to access Specification_for_Submission_Formats_for_eCTD_v1_0_.pdf

////////ICH M8, Specification, Submission Formats,  eCTD

EMA’s new Draft Guideline on the Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers

For medicinal products administrated in sterile form, the process to reduce the microbial level is a critical manufacturing step with regard to quality. The EMA has recently published the draft of a guideline on that topic which contains a range of clarifications. Read more about the coming requirements on sterilisation of medicinal products, APIs, excipients and final containers



As referred to in the European Pharmacopoeia, the procedure for terminal sterilisation of a medicinal product, an API, or an excipient is generally the method of choice. Yet, this might be difficult in many cases for product stability reasons. That’s why other microbial reduction processes can be used like sterilising filtration or aseptic processing. So far, there has been some uncertainty about these methods and their acceptance in a marketing authorisation procedure or a variation application, and about which data have to be submitted.

EMA’s new draft guideline entitled “Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container”  from April 2016 contains clear provisions with regard to the acceptance of alternative sterilisation processes by the European authorisation authorities. Those provisions apply to chemical and biological medicinal products for human and veterinary use as well as the respective APIs and excipients, but aren’t applicable for immunological veterinary medicinal products.

The document describes the requirements on sterilisation of medicinal products, APIs, excipients and primary containers, as well as on the choice of the method of sterilisation. Besides, the document contains two decision trees for the selection of the sterilisation method for products in diverse galenic forms.

Please find hereafter a summary of most important aspects in this chapter:

Manufacturing of sterile medicinal products
The conditions and physical parameters for the following processes are described in detail:

  • Steam sterilisation
  • Dry heat sterilisation
  • Ionisation radiation sterilisation (here reference is made to the Note for Guidance “The use of Radiation in the Manufacture for Medicinal Products“, ISO 11137 and Ph. Eur. Chapter 5.1.1)
  • Gas sterilisation (with ethylene oxide,  ethylene chlorhydrin, etc.)
  • Sterile filtration
  • Aseptic processing

Basically, the following rules apply to all processes:

  • The choice of the sterilisation method has to be justified.
  • The method must be validated.
  • The method described in the corresponding general monograph of the European Pharmacopoeia has to be used. All deviations have to be justified.
  • The procedures for all sites (including outsourced activities) where sterilisation is performed have to be documented (CTD module 3, chapters 3.2.P.2 and 3.2.P.3).

Manufacturing of sterile APIs and excipients
The document clarifies that the requirements laid down in Part II of the EU GMP Guide are only applicable for the manufacture beginning with the starting material up to the finished API, immediately prior to sterilisation. The sterilisation step performed on the API is considered to be a step in the manufacture of the medicinal product. As a consequence, each manufacturing establishment which performs sterilisation of an API requires a manufacturing authorisation, a GMP certificate and thus aQualified Person too. This also applies to establishments which manufacture sterile excipients. APIs and excipients with a Certificate of Suitability (CEP) are also covered by this regulation.

Selection of the sterilisation method
The following principles apply:

  • According to Ph. Eur., general chapter 5.1.1, the terminal sterilisation step should be made in the final container whenever possible.
  • When sterilisation by heat is not possible because of temperature sensitivity of the product, alternative methods or aseptic processing may be used if they are properly validated. Terminal steps for the reduction of the microbial level are also possible as long as they are not used to compensate for poor aseptic manufacturing practice.
  • A change (shortening) in shelf-life or storage conditions caused by the terminal sterilisation step is not in itself a reason to allow aseptic processing unless the new storage conditions or shelf-life would cause problems or restrictions in the use of the product.
  • An increase in impurity levels or degradation products upon terminal sterilisation doesn’t directly lead to the acceptation of aseptic processing. The risks induced by an increased level of impurities should be balanced with the risks induced with an aseptic manufacturing method (e.g. characteristics of the degradation products vs. posology of the medicinal product). Attempts performed to determine sterilisation conditions to give acceptable impurity levels and to simultaneously achieve a microbial reduction of at least 10-6 have to be described in the quality dossier.
  • Under specific conditions, aseptic processing may be accepted even if terminal sterilisation of the product itself would be possible, e.g. in the case of eye drops in polyethylene containers enabling administration of single drops or pre-filled pens. Here, terminal sterilisation of the product would destroy the final container.
  • The considerations for the choice of the container should be described in the dossier also in the case of heat-sensitive final containers. Here, the search for materials which come through terminal sterilisation has priority. For example, polypropylene is more resistant than polyethylene. The choice for the final container has to be justified.
  • Large volume parenterals should be terminally sterilised whenever possible.

In general, the regulatory authorities will expect a detailed justification for the selection of the sterilisation method or the aseptic processing in the form of a benefit/risk analysis.

The essence of the requirements described in the chapters of this guideline can be found in the two decision trees for sterilisation of products in diverse administration forms (aqueous liquid; non-aqueous liquid, semi-solid, dry powder).

The deadline for comments on this Draft Guideline Sterilisation of the medicinal product, active substance, excipient and primary container ends on October, 13th 2016.

///////////////EMA,  new Draft Guideline, Sterilisation of Medicinal Products, APIs, Excipients and Primary Containers

USP publishes draft of a new general chapter for plastic components used in manufacturing

In the Pharmacopoeial Forum (PF)  42(3) (May-June 2016) the USP General Chapters – Packaging and Distribution Expert Committee proposes a new general chapter  <661.3> Plastic Components and Systems Used in Pharmaceutical Manufacturing and a revised version of general chapter <1661> Evaluation of Plastic Packaging and Manufacturing Systems and Their Materials of construction with Respect to Their User Safety Impact. Read more about USPs Proposal on Plastic Components and Systems Used in Pharmaceutical Manufacturing.

<1661> Evaluation of Plastic Packaging and Manufacturing Systems and Their Materials of construction with Respect to Their User Safety Impact. Read more about USPs Proposal on Plastic Components and Systems Used in Pharmaceutical Manufacturing.



In the Pharmacopoeial Forum (PF)  42(3) (May-June 2016) the USP General Chapters – Packaging and Distribution Expert Committee proposes a new chapter to address the qualification of plastic components used in the manufacture of APIs (pharmaceutical and biopharmaceutical) and drug products (DPs). The proposed Title of the new chapter <661.3> is Plastic Components and Systems Used in Pharmaceutical Manufacturing. The draft is open for comment until July 31, 2016.

The chapter is part of a suite of chapters, including Plastic Packaging Systems and Their Materials of Construction <661>,Plastic Materials of Construction <661.1>, Plastic Packaging Systems for Pharmaceutical Use <661.2>, and Evaluation of Plastic Packaging and Manufacturing Systems and Their Materials of construction with Respect to Their User Safety Impact<1661>. In addition a section has been added to general chapter <1661> to support the use and understanding of the new general chapter <661.3>. The revision of general chapter <1661> (including change of title) also appears in the PF issue 42(3).

The chapter <661.3> addresses the qualification of plastic components used in pharmaceutical manufacturing and is applicable solely to those processes that involve liquid process streams and process intermediates due to the expected increased degree of interaction with liquids. Plastic manufacturing systems for pharmaceutical use include – for example – bags, cassettes, chromatographic columns, connectors, filling needles, filters, sensors, tanks, tubing, and valves.Elastomeric parts such as diaphragms, gaskets, and O-rings are not in the scope of this chapter. A flow diagram that shows a typical bioprocess DP production suite is shown in general chapter <1661>, Figure 2.

The manufacturer of APIs and DPs is responsible for ensuring that the plastic components and systems used are suited for the intended purpose. It is likely that raw materials, intermediates, process streams, APIs, and DPs will get in contact with one or more plastic component(s) of the manufacturing suite during the manufacturing process, resulting in process-related impurities (PrIs). PrIs have the potential to alter a quality attribute of the DP, if the PrIs persist through the manufacturing process.

Plastic manufacturing components and systems are chemically suited for their intended use with respect to safety if:

  • they are constructed from well-characterized materials that have been intentionally chosen for use as established by the test methods included in general chapter <661.1>;
  • The general physicochemical properties of the components have been established;
  • The biocompatibility (biological reactivity) has been appropriately established;
  • They have been established as safe by means of the appropriate chemical testing, such as extractables or leachables profiling and toxicological assessment of the test data (“chemical safety assessment”).

The chapter provides guidance on the appropriate application of biological reactivity tests (reference to general chapters <87>, <88>) and physicochemical tests (reference to Food Additive regulations and general chapter <661.1>, where applicable) for manufacturing components and systems. A two-stage approach consisting of an Initial Assessment followed by a Risk assessment leads to the required level of component characterization. The Initial Assessment examines the factors present for demonstration of equivalence with a comparator component or system by looking at the following parameters:

  • purpose and composition of component or system;
  • composition of DP(s);
  • processing conditions;
  • product dosage form.

The demonstration of equivalence would allow acceptance of the component (or system) without any further characterization. If equivalence cannot be established between the component (or system) under consideration and the comparator, then a Risk Assessment should be conducted. The risk assessment matrix is provided in detail in general chapter <1661>. The outcome of this assessment results in three risk levels: low (A), moderate (B), and high (C). These levels are linked according to the risk of the individual dosage form (e.g. solid oral and liquid oral, others than solid oral and liquid oral) to test requirements as shown in the draft chapter <661.3>. All three risk levels require identification of the component or system as specified in general chapter <661.1>. Identity is only required for those components or systems that consist of single materials of construction (individual polymers only). Biological reactivity testing according to USP general chapter <87> (In Vitro) is required for all levels plus testing according to Class VI in <88> (In Vivo) for Level B and C.  Level A and B require that the component or system be tested as specified in general chapter <661.1> for physicochemical characteristics and extractable metals characteristics. Level C components (or systems) must be characterized more rigorously than level A and B components in view of the extractables profile.
Additives: For level A components reference to 21 CFR Indirect Food Additive regulations is sufficient, for level B components additives are determined by testing, and for level C components extraction studies have to be performed.

After free registration in the Pharmarcopoeial Forum you can read the complete drafts of the new general chapter <661.3> and the revised chapter <1661>.

/////USP, draft,  new general chapter,  <661.3>, plastic components,  manufacturing

APIs from Legitimate and Reliable Sources

APIs from Legitimate and Reliable Sources

1. Introduction

Counterfeit and sub-standard APIs are increasingly present. Not only are they a fact of non-compliance but also they form a serious and increasing risk for patient safety. Various initiatives have been taken such as the founding of the FDA Counterfeit Drug Task Force, the European Commission’s current “Public consultation in preparation of a legal proposal to combat counterfeit medicines for human use” and the WHO Program “IMPACT” (International Medical Products Anti-Counterfeiting Taskforce).

API =Active pharmaceutical ingredient (synonym: drug substance)

Counterfeit API =Active pharmaceutical ingredient for which source and/or quality are falsely represented on the label, on the certificate of analysis or otherwise

Rogue API =API that is counterfeit or severely, deliberately non-compliant.

This writeup focuses on the interaction between the API manufacturer and the medicinal product manufacturer and provides possible measures that may be taken by both partners in order to ensure only non-rogue APIs are used in the manufacture of medicinal products. The proposed measures are considered as elements out of a whole puzzle. A risk-based approach should be applied to determine the necessity and value of the individual proposals, alone or in combination. The document does not address in detail the vendor qualification process as it is taken for granted that APIs are only purchased from suppliers that have been thorough checked

API manufacturer= Active pharmaceutical ingredient manufacturer

Medicinal product manufacturer= formulation manufacturer

Supply Chain

A supply chain is actually a complex and dynamicsupply and demand network. A supply chain is a system of organizations, people, activities, information, and resources involved in moving a product or service from supplier to customer.

2. Supply Chain:

Agents, Brokers, Distributors, Repackers, Relabelers As a general principle, the shorter the supply chain, the more secure it will be. This is reflected in the EU GMP Guidelines, Part 1 (5.26) specifying that starting materials (APIs, excipients) should be purchased, where possible, directly from the producer.

In addition to the length of the supply chain, any changes on the original container – e.g. by repackaging, relabeling – should be considered as an additional risk for alteration and should therefore, whenever possible, be avoided.

There is no doubt that the entire supply chain needs to be assessed from a quality perspective, covered by an effective supplier qualification program and the same principles as described in the following sections for the direct supply form API manufacturer to drug product manufacturer should be applied. This already starts at the point of selecting the contractor for transportation of the API (see also ICH Q7, 10.23).

3. On Site Visits / Audits



A thorough knowledge of the supplier is a key element. Therefore, a close and stable relationship between the manufacturer of the API and the drug product manufacturer should be achieved by using various means of contact. A regular exchange between 3/8 sourcing- and purchasing people and the supplier contributes to strengthening this relationship, especially if the contact also includes regular visits on site. Site visits should not be restricted to the manufacturing site alone; intermediaries in the supply chain should be covered as well. It should be ensured that representatives of the purchasing department have a good GMP- and regulatory awareness and technical understanding so that these visits are as beneficial as possible, also in relation to compliance.

Audits=Auditing refers to a systematic and independent examination of books, accounts, documents and vouchers of an organization to ascertain how far the statements present a true and fair view of the concern.

3.2. Audits

An audit is considered the most effective way of verifying concrete and compliant manufacturing incl. distribution of APIs. However, apart from the fact that an audit is very time-consuming it only provides a snapshot of the situation and there is no 100% guarantee that evidence for any occurring counterfeiting activities may be identified. Nonetheless, there are various elements in a quality audit that may increase that probability and that respectively may confirm the reliability of the manufacturer.

Counterfeiting activities= To counterfeit means to imitate something. Counterfeit products are fake replicas of the real product. Counterfeit products are often produced with the intent to take advantage of the superior value of the imitated product

3.2.1 General

Whenever possible, the audit should be executed when an actual production campaign is ongoing.

Requests for changing the agenda at short notice during the audit, e.g. revisiting areas on another time or day, may be a useful approach to confirm the consistency of operations on site.

Warehouse=A warehouse is a commercial building for storage of goods. Warehouses are used by manufacturers, importers, exporters, wholesalers,transport businesses, customs, etc

3.2.2 Warehouse

The walk-through in the warehouse supports the verification of the materials management capability with respect to claimed annual production of the API and storage capacity.

Checking for the presence of intermediates or APIs in the warehouse that have been purchased and could be subject for relabeling or of APIs intended to undergo a reprocessing may lead to the identification of different sources of materials than claimed. The list of approved vendors should also be reviewed for this purpose.

The review of the materials management system and material movements (booking in/out) of concerned API starting materials, intermediates and the final API is another possible source of information in the warehouse. However, confidentiality with respect to other customers’ names needs to be respected.

Production=the action of making or manufacturing from components or raw materials, or the process of being so manufactured.

3.2.3 Production

The walk-through in production should cover the verification of the necessary equipment and necessary utilities by cross-checking with the production instruction and/or process flow chart.

Document Review=Document review (also known as doc review) is the process whereby each party to a case sorts through and analyzes the documents and data they possess (and later the documents and data supplied by their opponents through discovery) to determine which are sensitive or otherwise relevant to the case

3.2.4 Document Review

The review of master production instructions as well as analytical methods and specifications for raw materials, intermediates and the API as well as of executed documents/raw data and cross-checks with the regulatory document (e.g. DMF, CMC section, CEP dossier) is an important element in verifying regulatory compliance.

One can also verify the availability of production records and/or analytical raw data as well as retained samples (where applicable) of raw material, intermediates and API batches for specific batches that were either identified from the review of the stock cards/materials management system, product quality review or from supplied batches.

The timely and sequential correlation of equipment use logbooks in production and QC laboratory, production batch records (incl. electronic raw data), cleaning records and analytical raw data (incl. date/time on equipment printouts such as balances, chromatographic systems etc.) is a good indicator for on site production.

The review of the documentation related to seals (specifications – testing/approval according to specifications – reconciliation documentation – authorized persons identified and documented…) may be added.

A spot wise review of analytical raw data from stability studies (not only the summary table) as well as of the logbook of the stability chambers (e.g. date of sample in/out) and the check for physical availability of the stability samples should be included.

The adequate involvement of the drug product manufacturer in case of changes that can impact the quality and/or regulatory compliance of the API may be verified by the reviewing the history of changes and individual change request cases related to the production and testing of the API (incl. intermediates, raw materials),

4. Supporting Documentation

The availability of certain documents that are regularly available and up-dated, where applicable, may be considered as one efficient element in the continuous supplier monitoring process.

Inspections=Inspections are usually non-destructive. Inspections may be a visual inspection or involve sensing technologies such as ultrasonic testing, accomplished with a direct physical presence or remotely such as a remote visual inspection, and manually or automatically

4.1 Inspections,

Inspection history As part of the initial evaluation of a potential API supplier the GMP inspection history, with respect to inspecting regulatory body, inspection date, inspected areas (as far as this information is / is made available) and the inspection results should be reviewed. A regular up-date of the inspection history as part of the supplier monitoring and requalification process should be performed. On the other hand, as these inspections are not mandatory for APIs e.g. used in medicinal products for the EU, the non-availability of an inspection history may not lead to the conclusion that this API supplier is less reliable. 5/8

GMP=Good manufacturing practices (GMP) are the practices required in order to conform to the guidelines recommended by agencies that control authorization and licensing for manufacture and sale of food, drug products, and active pharmaceutical products. These guidelines provide minimum requirements that a pharmaceutical or a food product manufacturer must meet to assure that the products are of high quality and do not pose any risk to the consumer or public.

4.2 GMP certificates

GMP certificates of the API manufacturer, where available (see 4.1), should be provided, ideally as authentic copies.

Certificate of Analysis=A Certificate of Analysis is a document issued by Quality Assurance that confirms that a regulated product meets its product specification. They commonly contain the actual results obtained from testing performed as part of quality control of an individual batch of a product.

4.3 Certificate of Analysis

A thorough review of Certificate of Analysis, against regulatory documents (e.g. DMF, CMC section, CEP dossier) and in-house specification respectively, and with respect to GMP compliance (ICH Q7, 11.14) should be performed as part of incoming release testing of APIs. Suppliers involved in counterfeiting could apply improper documentation practices. In case of agents, brokers etc. being involved in the supply chain it is recommended to insist on a certificate of analysis issued by the original manufacturer of the API (see also 2.). Where a new certificate of analysis is prepared by agent, broker, distributor, there should be a reference to the name and address of the original manufacturer and a copy of the original batch Certificate should be attached, as specifically required by ICH Q7 11.43, 44

4.4 Certificate of Compliance,

Compliance Commitment A certificate of compliance issued by the API manufacturer, either as a separate document or as part of the certificate of analysis, which certifies that a specific batch has been manufactured according to ICH Q7 GMP requirements and in line with the applicable Registration Documents can provide additional assurance related to the awareness of the manufacturer on the quality and regulatory expectations of the customers.

4.5 On-going stability program

A GMP compliant manufacturer has an on-going stability program for its APIs (ICH Q7, 11.5). At least one batch of the API manufactured per year is added to the stability program and tested at least annually. A regular up-date of the program provided by the API manufacturer, not necessarily including stability data, gives additional assurance for actual and compliant systems.

4.6 Product Quality Review

The major objective of the Product Quality Review (ICH Q7, 2.5) is to evaluate the compliance status of the manufacture (process, packaging, labelling and tests) and to identify areas of improvement based on the evaluation of key data. It includes a review of critical in-process controls and critical API test results, of batches that failed to meet specification, of changes carried out, of the stability monitoring program, of quality-related returns/complaints/recalls and of the adequacy of corrective actions. Due to the comprehensive information included, the Product Quality Review provides a good overview of the manufacture of a certain API.

The document should be reviewed during an audit or as a minimum an approved executive summary should be made available by the API manufacturer.

4.7 Quality Agreement

The quality agreement as a tool to clearly define the GMP responsibilities strengthens the awareness of liabilities of both partners. The extent and level of detail of the agreement may vary and can depend on the material supplied, e.g. generic API versus exclusively synthesized API, but it should at least address – name of the product – mutually agreed specification (if not covered by supply agreement) – manufacturing site – applicable cGMP standards, e.g. ICH Q7 – compliance with the DMF or with other registration documentation – GMP audits related to the API (e.g. 3rd party auditing) – documents to be provided by the manufacturer, e.g. certificate of analysis, certificate of compliance, inclusion of copies of respective master documents may be addressed – arrangements for transportation and transport packaging (see 5.), e.g. description and degree of tampering proof seal to be used, inclusion of a copy of the master drum label may be considered – deviation handling – handling of and response to complaints – change management: involvement of the customer with respect to notification and approval – list of approved signatories may be included

5 Packaging:

labeling, tamper-proof sealing If the API manufacturer provides examples/templates of master labels, which he uses to label the containers, this supports the drug product manufacturer in identifying any manipulation on the material on its way from the manufacturer to the recipient.

The use of tamper-resistant packaging closure by the manufacturer provides additional assurance that the material was not adulterated on its way from the manufacturer to the drug product manufacturer. A manufacturer-specific design of the seal is recommended to be used; the use of unique seals may be considered. The communication of the type of seal, by the manufacturer to the user, completes the information chain.

Material Inspection = Critical appraisal involving examination, measurement, testing, gauging, and comparison of materials or items. An inspection determines if the material or item is in proper quantity and condition, and if it conforms to the applicable or specified requirements. Inspection is generally divided into three categories: (1) Receiving inspection, (2) In-process inspection, and (3) Final inspection. In quality control (which is guided by the principle that “Quality cannot be inspected into a product”) the role of inspection is to verify and validate the variance data; it does not involve separating the good from the bad.

Sampling= Sampling is the process of selecting units (e.g., people, organizations) from a population of interest so that by studying the sample we may fairly generalize our results back to the population from which they were chosen.

6. Material Inspection, Sampling, Analysis, Impurity Profile

At the point of receipt the first relevant action is to carefully perform the visual inspection of all the containers of the API. Attention shall be paid to the integrity and type of the sealing as well as to the special attributes added by the manufacturer (see above 4.7, 5.) such as label design, seal number and design.

The applied sampling regime related to the number of containers sampled, number of samples taken per container, analysis of individual and/or pooled samples as well as the extent of analysis, varying from identity test to full analysis may influence the probability of identifying counterfeiting, provided it may be identified by analytical means.

A risk-based approach, considering the qualification status of the supplier, may be chosen to define the extent of sampling and testing, considering the requirements for drug product manufacturers (e.g. Annex 8 to EU GMP Guidelines). 7/8 The impurity profile is normally dependent on the production process and origin of the API. The comparison of the impurity profile of a current batch with either previous batches or data provided by the manufacturer (e.g. as part of the regulatory submission) may help in order to identify changes related to modifications in the production process and may indicate whether the API might originate from a different manufacturer than the supposed one.

It is recommended to check the current (im)purity profile and compare it with former quality in regular intervals, at least once a year


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FDA issues rule for data collection of antimicrobial sales and distribution by animal species

New Drug Approvals

05/10/2016 09:28 AM EDT
Additional data help further target efforts to ensure judicious use of medically important antimicrobials
The U.S. Food and Drug Administration (FDA) finalized a rule today that revises its annual reporting requirements for drug sponsors of all antimicrobials sold or distributed for use in animals intended for human consumption or food-producing animals. Companies are now required to provide estimates of sales broken down by major food-producing species (cattle, swine, chickens and turkeys) in addition to the overall estimates they already submit on the amount of antimicrobial drugs they sell or distribute for use in food-producing animals.

May 10, 2016


The U.S. Food and Drug Administration finalized a rule today that revises its annual reporting requirements for drug sponsors of all antimicrobials sold or distributed for use in animals intended for human consumption…

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