Archive for the ‘Regulatory Affairs’ Category

A discussion of the advantages and disadvantages of the different methods used in pharmacovigilance.

Wednesday, October 17th, 2012

Medicines should fulfill the aspects of quality, safety and efficacy. The objectives of obtaining pharmacovigilance data are to improve patient care and safety, to improve public health and safety in relation to the use of medicines, to contribute to the assessment of benefit, harm, effectiveness and risk of medicines, to encourage their safe, rational and more effective use by identify signals of previously unidentified adverse reactions to medicines, to promptly identifying events that are likely to affect adherence to treatment and to determine their rates and the risk factors that make these events more likely. It is important to be able to estimate rates of events so that risk can be measured and informed decisions can be made regarding appropriate treatments where comparables exist, whilst considering the risks they carry. There is relatively little data available regarding the safety of medicines in pregnancy or lactation, nor indeed in paediatric populations, so data obtained in these subgroups is extremely valuable.

Case reports are often the main source of information from which data is derived to trigger the withdrawal of a drug from the market for safety reasons. However, in order to have quality evidence to support such decisions, it is necessary to improve the volumes of reports received. More and more focus is being placed on pharmacovigilance, and over the last few years this has driven change for example via policies on risk management plans, and also by pharma companies via pharmacogenomics in development programs. More efforts are now being placed on predicting risk, rather than minimising negative outcomes in a reactive manner. This move is very promising and in order to ensure a consistent approach for both pre-marketing and post-marketing pharmacovigilance activities, companies are beginning to incorporate risk management planning at the inception of Phase I and to consider consolidating both their pre- and post-marketing pharmacovigilance activities into a single department.

The method of monitoring of trials should be carefully chosen and should reflect the requirements of the study. Monitoring can involve cohort event monitoring, spontaneous reporting and special phase IV studies or post marketing surveillance studies. The phase of the drug in its lifecycle will often determine the post appropriate method. For example, a new chemical entity at pre-marketing authorisation stage should be subjected to clinical trials and at this stage all suspected unexpected serious adverse reactions (SUSARs) are reported. The sponsor is obliged to report such events to the concerned member state, the ethics committees and via the Eudravigilance system electronically.(1) Post receipt of marketing authorisation, adverse reports are required to be submitted as “Individual Case Safety Reports” (ICSRs) within specified timelines. A serious unexpected ADR must be reported within 10 working days of receipt. (2) Post-marketing surveillance is very important, because the safety database for newly licensed drugs is limited by both the number and characteristics of the patients involved.(3) Periodic safety update reports (PSURs) are required from marketing authorisation holders to be submitted to the competent authorities as per the timescale applicable to the active and drug in questions. These consist of non-serious, serious, not related and deaths.(4) Unfortunately, in reality, no one method can be relied upon for global signal detection, but rather they all complement each other in building the bigger picture.

Randomised clinical trials cannot provide an adequate safety profile; they are short-term studies with often short comings when it comes to recording delayed reactions, withdrawal effects, changes in death rates, dose variations, data on women and in unlabelled use. Trials are generally not designed for the purpose of assessing adverse events. Premarketing clinical trials include too few patients and are too short to detect every outcome that will affect public health and individual patient safety. In addition, clinical trials are carried out in controlled settings that differ from real world practice. This reduces their power to detect ADRs, such as those that are due to drug-drug interactions or that affect only susceptible subgroups. Safety needs to be evaluated continuously throughout the life-cycle of a medicinal product and adverse event data derived from such clinical trials may suggest that further research on adverse events is worthwhile. For this reason, a study cohort may be chosen with variables. Where cohort event monitoring is selected as the principal means of monitoring, there are distinct advantages to encouraging spontaneous reporting also. Contemporaneous cohorts of other medications may provide some kind of control, but the lack of specially selected controls is a drawback in both determining causality and attributable risk. Coding strategies may obscure outcomes, as they may with ICSRs. However, the advantages of cohort monitoring outnumber any disadvantages and include the fact that it data can be used to derive rates of adverse events, to obtain an adverse event profile for the medicine, to identify early signals and to characterise adverse events in relation to age, sex and duration to onset and thus produce risk factors. This may lead to the collection of other relevant data, such as weight, or co-morbidity, to enable other risk factors to be determined. The disadvantages are due to this method being more labour intensive and more costly than spontaneous reporting. Cohort event monitoring allows for a different capture of events which may or may not be medication related. As such, unusual clinical events may be found to have a relationship to a medication, which might not be obvious to the users and reporters. These signals may be seen by the remote observer evaluating collated cases, quantified in a continuous known cohort of exposed individuals. It enables accurate comparisons to be made between medicines and allows a pregnancy register to be established that can be used to define and calculate rates of any abnormalities. The routine follow-up enables quite a confident detection of reduced or failed therapeutic effect and thus can raise suspicion of inaccurate diagnosis of disease, programme failure, or poor quality or counterfeit medicines. Details of deaths can be recorded and examined and it provides data on death rates. It has the ability to produce rapid results in a defined population. It enables the collection of comprehensive and near-complete data that will provide for the special needs of the program including effects in pregnancy, specific toxicities and safety in children. Because the method looks intensively at new medicines of great interest in a specific area of need, and provides clinically significant results rapidly, it stimulates interest in medicine safety in general. The method provides sound evidence with which to deal with any medicine scares.

The advantages associated with spontaneous reporting include the fact that it is administratively simpler and less labour intensive than cohort event monitoring, it is less costly, easy to implement, is applicable to all medicines, rare reactions can be identified and it is the method most commonly used in pharmacovigilance and National pharmacovigilance centers. Healthcare professionals are more familiar with the method also. This mechanism accepts both healthcare professional and consumer reports and both sources can contribute to the regulation of medicines. The disadvantages associated with this are that the data is often incomplete. There is often no denominator available, delayed effects may go unnoticed and sometimes common clinical problems are not linked to drug to the drug in question. These reports are reported voluntarily, bias can exist, there is no control group and there can be differential under-reporting. So unfortunately, reliable rates cannot be calculated and therefore risks and risk factors cannot be established with confidence. For this reason, there is obvious need for special studies to collect accurate information on areas of particular interest e.g. pregnancy, children and the elderly. These special studies add to the overall cost and reduce the cost advantage of spontaneous reporting.

The databases used for storing this data, also requires significant attention. The use of large databases for analyses is the most efficient and reliable method and the implementation of such databases in different countries could increase the quality of the information on adverse drug reactions (ADRs) by allowing researchers to conduct efficiently various types of studies They would also permit wider accessibility for researchers. The ability to understand and prioritize the most important data, and to use data mining to evaluate it is very advantageous. In Europe, the Eudravigilance system consists of one common electronic reporting point within the European Union that is advanced. This harmonised system is compliant with ICH E2B (M), M1 and M2 standards. The advantage of this system is ease of use and fast reporting mechanisms both from reporters, but also between health authorities. Unfortunately, despite significant globalisation of pharmaceutical companies and many of the same drugs being available in the main territories, adverse event data is not shared routinely between territories. However, the FDA for example will accept data from clinical trials carried out abroad if they are conducted ethically and in accordance with requirements.(5) It is expected that there is a possibility that the US and EU may seek to share such data going forward and this would offer a significant benefit should this happen. It would allow access to data derived from a broader exposure in these populations.

In conclusion, monitoring does carry a cost, though there are advantages to gathering data which can drive evidence-based decisions on medicine selection, produce sound data with which to respond to any medicine scares in an informed manner, minimize adverse effects which might affect patient safety and adherence by determining risk factors and the means for risk prevention, allow early identification of inefficacy or treatment failure, identify medicine–medicine, medicine–disease or medicine–food interactions. Costs are normally associated with staff, training, communication, information systems, production of promotional literature, and production of reporting forms. Monitoring involves many stakeholders including the ministers of health, regulatory authorities, national pharmacovigilance centre, the WHO monitoring centre, the European Medicines Agency (EMEA), academia, hospitals, schools of medicine, pharmacy and nursing, professional organizations, health professionals who are to participate, pharmaceutical companies, patients, media, patient support groups where these exist, general public.



1. Volume 10 Eudralex Clinical trials guidelines

2. ICH Topic E 2 A. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. Note for Guidance on Clinical Safety Data Management Definitions and Standards for Expediting and Standards for Expedited Reporting. June 1995 CPMP/ICH/377/95

3. Mann RD. Prescription-event monitoring -recent progress and future horizons. Br J Clin Pharmacol1998; 46: 195-201.

4. Volume 9A Eudralex. Pharmacovigilance guidelines.

5. Code of Federal Regulations. Title 21, Volume 5. Revised as of April 1, 2009. 21CFR312.120. Investigational New Drugs. Foreign clinical studies not conducted under an IND.


Wednesday, October 17th, 2012

According to the EMEA “A biosimilar medicine is a medicine which is similar to a biological medicine that has already been authorised (the “biological reference medicine). (1) According to the US Price Competition and Innovation Act 2009, “A biosimilar is a biological product that is highly similar to the reference product, not withstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product in terms of the safety, purity and potency. This Act also addresses the complexity of biologics as large complex molecules whose manufacture typically exhibits at least minor degrees of structural and functional variability.(2) A well defined regulatory pathway was created in Europe since 2005. To date, products such as somatropin, epoetin and, filgrastim have been approved as biosimilars. Indeed, Reuters reports that biosimilars are becoming a commercial reality for Novartis. Revenue from generic enoxaparin, a biosimilar of Sanofi-Aventis’ anticoagulant Lovenox, was valued at $292 million in 3Q10 and the product is on track to achieve blockbuster status, with annual sales above $1 billion. In the USA, it remains to be established how biosimilars will be regulated, though a legal pathway has been established. Progress is similarly underway in Japan and elsewhere. In the US, in March of this year, President Barack Obama signed the broad-based healthcare reform package into law and this was the foundation for the legal basis of biosimilars. The base approach is to be consistent across EU and US remits and the biological products will need to show that they are biosimilar to a reference product. For the purpose of this discussion, the experience in Europe will mostly be used, since the CHMP has more experience to date in this area. Although no biosimilar mAbs have been approved to date in Europe, a concept paper has been issued by EMEA on this subject.(3)

 Biosimilar applications can be submitted to authorities, once the original medicine is no longer within the period of data protection. They are required to undergo scientific evaluation to assess efficacy, quality and safety. Whilst biosimilar applicants can make reference to the biological reference medicine, they do need to illustrate similarity via studies. Nevertheless, the package required for submission is less than that required for a full marketing authorisation application. It is not considered possible to produce identical biological products using manufacturing processes and the process for generics cannot be applied for biotech products. Required studies include additional clinical and non-clinical data to demonstrate equivalent safety and efficacy profiles to the originator product and a combination of physico-chemical and biological data. Such studies involve comparison of the quality and the consistency of the medicinal product and of the manufacturing process. Aggregates can form during manufacture, on storage or during reconstitution and are often associated with Mabs due to their high concentrations for therapy and the immunoglobulins that tend to aggregate. For this reason, appropriate formulation studies need to be performed to find an optimal formulation that is stable with respect to formation of particulates at release and during storage. Mabs by their nature are significantly larger than other biotech medicines. However, monoclonals are also being included for biosimilar applications. The EMA Concept paper underpins this. (4) Most of the therapeutic antibodies are humanized or human Immunoglobulins (IgGs) and are produced as recombinant glycoproteins in eukaryotic cells. Although IgGs glycans comprise of only about 3% of the total mass of the molecule they are involved in essential immune effector functions. However, they may also be allergenic, immunogenic and accelerate the plasmatic clearance of the linked antibody. For this reason, the glyco-variants have to be identified, controlled and limited for therapeutic uses. “Glycosylation depends on multiple factors like production system, selected clonal population, manufacturing process and may be genetically or chemically engineered.”(5) The glycosylation patterns observed for the current approved therapeutic antibodies produced in mammalian cell lines, classical and state-of-the-art analytical methods used for the characterization of glycoforms and the expected benefits of manipulating the carbohydrate components of antibodies by bio- or chemical engineering as well as the expected advantages of alternative biotechnological production systems developed for new generation of therapeutic antibodies and Fc-fusion proteins should be considered. Their primary structure must be compared to the reference product. Techniques such as MS-MS, C and N terminal sequencing, amino acid analysis and gene sequencing can underpin such characterisation. Techniques such as circular dichroism (CD), Fourier transform infra-red spectroscopy (FTIR) and micro-calorimetry have been used to differentiate between structures. Studies are also conducted to compare the safety and efficacy of the medicines. These studies should demonstrate that there are no meaningful differences between the biosimilar and the biological reference medicines in terms of safety or efficacy.

Whilst physico-chemical and biological studies can support applications, there remains the requirement to illustrate clinical safety. The safety of biosimilars should discount any toxicity in terms of immunogenicity, pharmacokinetics and pharmacodynamic effects. The CHMP nonclinical and clinical comparability guideline, stresses the need for in-vivo nonclinical studies. However, species specificity can be a barrier, as can the size and length of the study and also immunogenicity. Mostly monkeys are the preferred species to obtain nonclinical data and to provide the initial assurance that the biosimilar is safe to enter clinical trial in humans. The value of transgenic species must be considered since they are not validated models and in addition the value of nonclinical studies with regards to toxicity testing. For biosimilars, the value of nonclinical studies should also be considered and emphasis should be placed on knowledge of the toxicity associated with mechanism of action and unspecific toxicity, based in impurities. In-vitro studies should be utilised over animal studies in general. The level of glycosylation affects the Fc effector function i.e. the Fc region of the immunoglobulin from binding to the target receptors. For this reason, in-vitro potency assays are often used, which enable a comparison of the reference against the biosimilar as a functional level. However, for Mabs this is further complicated, since antibodies can bind not only to the target epitope but also with immune cells and complement. Changes in conformation of the protein can affect receptor affinity and expose epitopes. This can affect immunogenicity and lead to cell destruction or cytotoxicity. Immunogenicity monitoring does not differ from the reference production to the biosimilar product.(6) Comparative safety studies are required and it is not acceptable to use historical or literature based data. Changed glycosylation patterns can affect bioactivity such as defucosylation. The CHMP requests in-vitro and in-vivo studies, including receptor bind and cell based assays. Other considerations are the level of deamidation, oxidation and C terminal lysine processing. Variants can also be detected via SDS PAGE (sodium dodecyl sulphate polyacrylamide gel electrophoresis) SE-HPLC (size exclusion high performance chromatography) and analytical ultra-filtration. The challenge is to understand the significance of any differences between the reference medicine and the biosimilar. However, according to CHMP any difference in amino acid sequence or primary structure means that a protein must be treated as a different entity and therefore is not biosimilar. Mutagenicity, animal reproduction and carcinogenicity studies tend not to be required. Regulators are also concerned that despite understanding structure function activity, that physico-chemical and biological studies may not be sufficient to demonstrate safety and efficacy. For this reason, often Phase I studies are carried out on manufacturing scale batches and formulation. The phase I studies tend to be carried out in healthy volunteers, though sometimes ethical considerations must be considered as for Mabs where PK comparison of single treatments may not be appropriate. Therefore, phase III may only be possible in these instances. The EU CHMP Guideline should be considered in this context.(7)

In addition, the reference product should be sourced from the EU, if the biosimilar application is for submission in Europe. The FDA has still to define the level of flexibility in this context and if they will allow the use of non US reference products in pivotal clinical trials. When it comes to efficacy, the CHMP nonclinical and clinical guideline should also be considered. For biosimilars, it is important to note that the emphasis is on providing evidence for therapeutic equivalence, through understanding the structure, impurity profile and biological, nonclinical and clinical properties, along with an understanding of impact on the safety and efficacy. The three main classes of biosimilars approved in Europe to date are the human growth hormone (HGH), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF). For biosimilars such as somatropin, epoetin and G-CSF all the indications were approved as for the reference product. For MAbs, this is more complicated, since there needs to be an understanding of the mechanism of action, the therapeutic effect may depend on blocking the target receptor, interference with downstream signaling and eliciting an immune response. Also, tools such as pharmacodynamic markers and clinical endpoints for the assessment of safety and efficacy in target population need further development. Short-term efficacy studies with surrogate clinical endpoints can support this. Placebo trials are not ethical, therefore the focus is on non-inferiority or equivalence trials. Two products are never 100% equivalent and the ICH E9 addresses this point. (8) ICH E9 states “this margin is the largest difference that can be judged as being clinically acceptable and should be smaller than differences observed in superiority trials of the active comparator.” So where a Mab is demonstrated to have similar physico-chemical and biological properties, similar invivo and in-vitro effects, the efficacy is almost certain to be similar to that of the reference product. It will be interesting to see if the FDA will permit the extrapolation of indications where comparable safety and efficacy of the biosimilar product to the reference product is demonstrated in for example one or two sensitive patient populations. Biosimilar medicines are manufactured following the same quality standards as for all other medicines.

The relationship between the structural characteristics of the protein and its functions, as well as the ability to demonstrate structural similarity between the follow on protein and the reference product are predictors of clinical comparability and as such, many companies will have to pursue more intensive clinical studies until the level of scientific understanding and technology advances to support such understanding. The choice of reference standards to be used from pre-clinical to clinical stages, differences in method of manufacturing including cell line, purification processes, in-process controls, analytical methods and specifications for in-vitro comparability, immunogenicity test methods and validation and comparative pharmacology and toxicology studies including species selection and scope of studies, first in human trials Phase I for comparative assessment of safety, tolerability and PK/PD profile will all play a part in supporting biosimilar applications.




  1. EMEA. Doc. Ref. EMEA/74562/2006 Rev. 1. London, 22 October 2008.
  2. Woodcock J. Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States. Statement before the Subcommittee on Health Committee On Energy and Commerce United States House of Representatives, May 2, 2007.
  3. Committee for Medicinal Products for Human Use (CHMP). Concept Paper on the development of a guideline on similar biological medicinal products containing monoclonal antibodies. European Medicines Agency (EMEA); October 22, 2009.
  4. CHMP Concept Paper on Development of a Guideline on similar biological medicinal products containing Monoclonal Antibodies (EMEA/CHMP/BMWP/632613/2009 EMA) October 2009
  5. Beck A, Wagner-Rousset E, Bussat MC, LokteffM, Klinguer-Hamour C, Haeuw JF, Goetsch L, Wurch T, Van Dorsselaer A, Corvaia N. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol 2008 Dec;9(6):482-501.
  6. Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins (CHMP/BMWP/14327/06) effective April 2008, and Concept Paper on Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vitro Chemical Use (EMEA/CHMP/BMWP/114720/2009), Committee for Medicinal Products for human use (CMPH), European Medicines Agency., CHMP/437/04, October 2005.
  7. CHMP Guideline on Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substances Nonclinical and Clinical Issues (CHMP/42832/05) effective June 2006.
  8. ICH E9, Statistical Principles for Clinical Trials.

Updated Legislation Affecting Food Supplements

Thursday, February 4th, 2010

Directive on Nutrition Labelling 90/496/EEC and as amended by Directive 2003/120/EC, as well as the Food Supplements Directive 2002/46/EC and Commission Directive 2008/100/EC dated 28 October 2008 which also amends Council Directive 90/496/EEC on nutrition labelling for foodstuffs covering recommended daily allowances (RDAs), energy conversion factors and definitions. The amendments include a definition of fibre (for the first time in European law), the introduction of a calorific value (2 kcal/g – 8 kJ/g) for fibre and 0 kcal/g – 0 kJ/g for erythritol, and the revised table of RDAs for vitamins and minerals. Amendments are required to be implemented by 31st October 2012.

Classification of medicinal products, herbal and homeopathic medicines, food supplements and novel foods

Thursday, February 4th, 2010

Food supplements are currently regulated in Europe under the EC Food Supplements Directive 2002/46/EC, which has applied since 2005. Food supplements fall under the definition of ‘food’ under general food law. As such, in addition to the legislation which regulates food supplements specifically, food supplements must also comply with any other food law applicable to the product concerned, including general food labelling requirements. For food supplements, also nutrition and health claims must comply with Regulation (EC) No. 1924/2006. Food law places the onus for compliance on food business operators e.g. manufacturers, importers, wholesalers, retailers etc.  There are no defined legal requirements for GMP for this category. However, Good Manufacturing Practice (GMP) tends to be taken as the industry standard. There are legally defined requirements for Hazard Analysis for Critical Control Points (HACCP) based on the Food Hygiene Regulations 852/2004 and also there is the General Food Law regulation 178-2002 which places emphasis on traceability. As regards the ingredients in these products, food law works in such a way that if a product is considered to be medicinal, then it cannot be sold as a food. As regards health claims, food law prohibits properties being attributed to any food, including a food supplement, to the effect that it can treat, prevent or cure a human condition. Such claims would also make a product a ‘medicinal product’ under medicines legislation.

A novel food, unlike the term ‘food supplement’, is not a name under which a food can be marketed. ‘Novel food’ is a term used for foods which do not have an established history of use in the European Union prior to May 1997. Novel foods must undergo a safety assessment and be approved at European level before they can be placed on the market in the EU and must also meet food law obligations. A novel food catalogue has been created which contains information on foods and food ingredients that has been collected since the Novel Food Regulation entered into force.

At a European level the EMEA and at a national level the national health agencies are responsible for the regulation of medicines. The definition of ‘medicinal product’ also includes “…any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis”.  Of course GMP applies to all medicinal products.

 Alternatively, if the product is deemed to be a herbal product a “Certificate of Traditional-use Registration” (as per article 16a of Directive 2001/83/EC as amended via the Traditional Herbal Medicinal Products Directive (2004/24/EC) may apply.  Products in this category are registered under the Traditional Herbal Medicinal Products Registration Scheme and are known as traditional herbal medicines. A significant number of medicinal products despite their long tradition of use do not fulfil the requirements of a well-established medicinal use, with recognised efficacy and acceptable levels of safety and therefore cannot fulfil the requirements for a full MA as per article 8(3) for a full authorisation or article 10a for well-established use authorisation, of Directive 2001/83/EC as amended). 

 Homeopathic Medicines are distinct from other types of medicines, such as Herbal Medicines or Pharmaceutical Drugs, although they can be prepared from these sources.  This distinction comes from the methods used in their preparation as well as the principles on which they are prescribed. In 1992 the EC Directive 92/73/EEC, taking into account the unique nature of Homeopathic Medicines, (high dilution factor), made provision for a simplified registration procedure, for these medicines, to be implemented in Member States.

The Irish Medicines Board (IMB) is responsible for the classification of medicines in Ireland (except for controlled drugs and products authorised through the centralised procedure). For medicinal products, classifications include prescription (Rx) which includes renewable or non-renewable prescriptions, over the counter (OTC) or general sale (GSL). Herbal and homeopathic classifications can also apply.

European Pharmacopeia:

Thursday, February 4th, 2010

The Ph.Eur is recognised as the only official Pharmacopeia in Europe and is used for international trade. There are 19 observer countries and the World Health Organisation (WHO). It is presented in English and French. Directives 2001/83/EC, 2003/63/EC and 2001/82/EEC make mandatory the Ph.Eur monographs for quality specifications, Quality Control (QC) and terminology.  Raw material preparations, dosage forms, containers must comply with the Ph.Eur requirements where they exist. Certification is considered by regulators to be the preferred option. Harmonisation at an international level between the JP, EP and USP is progressing, though slowly. 45 monographs have been harmonised to date, though the basis for harmonisation can be cumbersome.

Named Patient and Compassionate Use

Thursday, February 4th, 2010

In Ireland the legal term is “exempt medicinal product” whilst it is referred to as  “specials” in the UK. The definition of “exempt medicinal product” means a medicinal product to which paragraph 2 of Schedule 1 to the Medicinal Product (Control of Placing on the Market) Regs2007, or any equivalent legislation in any other EEA State, applies. This is to say that Paragraph 2 of Schedule 1 specifies that Regulation 6 “shall not apply to the sale/supply of medicinal product in response to a bona fide unsolicited order, formulated in accordance with the specifications of practitioner for use by his individual patients, in order to fulfil special needs of those patients, but such sale/supply is subject to conditions in Para 3” (i.e. that the licensing requirements can be waived in this instance.)   


• S.I. 539/07 Medicinal Products (Control of Manufacture) Regulations 2007:

• S.I. 540/07 Medicinal Products (Control of Placing on the Market) Regulations 2007: