Catch up with the latest regulatory news from around the pharmaceutical industry with our November 2022 regulatory review, curated by Dr Tim Sandle.
BY DR TIM SANDLE | 30 NOVEMBER 2022
Good distribution practice New edition of the British Pharmacopeia
The British Pharmacopoeia (BP) 2023 edition, from the Medicines and Healthcare products Regulatory Agency (MHRA), is available and it contains the authoritative official standards for UK pharmaceutical substances and medicinal products.
According to the MHRA: “If a pharmaceutical substance or finished product is marketed in a country where the BP is a legal standard, it must comply with the requirements of the BP throughout its shelf life.”
For the new edition there are:
- 23 new BP monographs, 59 new Ph. Eur. monographs
- 151 amended BP monographs
- All monographs from the Ph. Eur. 10th edition as amended by supplements 10.1 to 10.8 are included
- The Ph. Eur. 11th edition, as amended by supplements 11.1 and 11.2 are included as in-year online and download product updates
11th edition of the European Pharmacopeia
On 1st January 2023, the 11th edition of the European Pharmacopeia comes into force. The main edition and the first supplement have been issued, enabling planning for their implementation to begin.
A selection of the updates, those most likely to be of interest to RSSL website visitors, have been highlighted below.
General notices
Chapter 1.1.2.1 has been updated in relation to the scope, shelf life and retest period. Here the statement has been rephrased to state that for some substances (that is, substances known to be labile (easily broken down or displaced), biotechnological/biological substances and certain antibiotics) a shelf life is established rather than a re-test period.
Chapter 2.1.3. Ultraviolet ray lamps for analytical purposes
Since mercury lamps are seldom used nowadays, alternatives have been added to reflect current laboratory practices. Alternatives to mercury include UV LEDs, excimer lamps (e.g., krypton-chlorine systems producing so-called far UV-C light) and xenon flash lamps (often referred to as pulsed UV-C systems).
Chapter 2.2.46. Chromatographic separation techniques
Chromatography is based on the principle where molecules in mixture applied onto the surface or into the solid, and fluid stationary phase (stable phase) is separating from each other while moving with the aid of a mobile phase. As a laboratory method it is a useful analytical tool for establishing the components of a drug's formulation, enabling researchers to quantify the formulation and discover whether there are any impurities in a product.
The pharmacopeia text has undergone a general revision, but compared to the last publication the principal changes are the following:
- Symmetry factor has been revised: 0.8-1.8 instead of 0.8-1.5.
- A statement that retention times and relative retentions are not requirements but given for information in the monographs has been added.
- System repeatability in assay: applicable to both active substances and excipients.
- Adjustments of the stationary phase, column dimensions, mobile phase, flow rate, injection volume (isocratic and gradient liquid chromatography); under conditions much stricter than in the current text, a UHPLC column may be used instead of an HPLC one.
- Adjustments of the column dimensions, injection volume and split ratio, injection port and transfer-line temperatures (gas chromatography).
- Adjustments for supercritical fluid chromatography deleted as technique not used in the Ph. Eur.
Vaccines for veterinary use (0062)
With the monograph on vaccines, in relation to bacteria and fungi (section 3-8) specific requirements for non-liquid vaccines for non-parenteral use have been added. The sterility requirements may be replaced by absence of relevant pathogenic microorganisms and an appropriately low number of contaminating microorganism based on batch data and process validation, provided that the product remains stable throughout its shelf life.
Radiopharmaceuticals
With the monograph for tetra-O-acetyl-mannose triflate for radiopharmaceutical preparations (2294), for the related substances/assay section the column used in the LC procedure for the related substances test and for the Assay is no longer available in the required quality. A new and much faster LC procedure is proposed using a different column.
Testing of nitrogen
With the monograph for nitrogen (1247) and the assay requirements, the detection temperature of 130 °C was considered unsuitable for certain instrumental setups. This has been replaced by a constant temperature within the range of 50 °C to 200 °C. The instruction to adjust the injected volumes and operating conditions so that the height of the peak due to nitrogen in the chromatogram obtained with reference gas (a) was at least 35 per cent of the full scale of the recorder was replaced by the instruction to inject 1 mL of the gas. With modern instrumentation recorder adjustment is no longer relevant.
Paraffin and harmonisation
For paraffin, white soft (1799) the contents now correspond to the sign-off text signed by the Pharmacopoeial Discussion Group (Ph. Eur., JP, USP). The coordinating pharmacopoeia is the USP.
Non-harmonised attributes have been placed between black diamonds (♦ ♦), while local requirements only present in the Ph. Eur. text have been placed between white diamonds (◊ ◊).
The main changes are:
- Definition: the statement concerning unsuitability for oral use has been introduced as a local attribute since this reflects regulatory requirements in Europe
- Characters: slight clarifications introduced to harmonise the wording
- Identification: 2nd identification is flagged as a local attribute. IR preparation is simplified
- Drop point: procedure slightly modified to improve the melting of the substance
- Appearance: the description of the test modified to align the three Pharmacopoeias
- Consistency: test moved to the FRC section as it is considered appropriate to assess the functionality of white soft paraffin used as a basis in semi-solid preparations
- UV absorbance limit for polycyclic aromatic hydrocarbons: limit decreased based on proposal for international harmonisation (specification to cover limits by FDA 21CFR172.880). Path length adjusted to reflect standard cells with 1 cm
A similar harmonisation process has been completed for ‘Paraffin, yellow soft (1554)’. The changes are:
- Definition: the statement concerning unsuitability for oral use has been introduced as a local attribute since this reflects regulatory requirements in Europe
- Characters: slight clarifications introduced to harmonise the wording. Section is flagged as non-harmonised
- Identification: 2nd identification is flagged as a local attribute. IR preparation simplified
- Drop point: limits and procedure slightly modified to improve the melting of the substance
- Appearance: the description of the test modified to align the three Pharmacopoeias
- Consistency: test moved to the FRC section as it is considered appropriate to assess the functionality of yellow soft paraffin used as a basis in semi-solid preparations
- UV absorbance limit for polycyclic aromatic hydrocarbons: limit decreased based on proposal for international harmonisation (specification to cover limits by FDA 21CFR172.880). Path length adjusted to reflect standard cells with 1 cm
The difference between white soft and yellow soft paraffin relates to absorbance. To determine the different, laboratories measure the absorbance of a 1-cm layer at about 290 nm. White soft paraffin does not exceed 0.5 and yellow soft paraffin does not exceed 0.75.
Sucrose (0204)
With the sucrose monograph, functionality-related characteristics have been updated. This is with the addition of a section for sucrose used as filler/diluent in solid dosage forms, cross-reference to Particle-size distribution and bulk and tapped density.
Pre-approval inspections
A pre-approval inspection is performed to contribute to regulatory assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete. The U.S FDA released two updated compliance programme guides (CPGs) covering pre-approval inspections (PAIs) and routine good manufacturing practice (GMP) surveillance inspections.
The updates relate to FDA’s use of alternative tools for evaluating facilities in lieu of onsite inspections used during the pandemic, as well as new sections covering nitrosamine risk assessments (RAs) and relevant ICH guidelines.
- CPG for PAIs, 7346.832: incorporates ICH Q10 guideline on pharmaceutical quality systems, the ICH Q12 guideline on postapproval changes, and addresses nitrosamine RA, see Guidance for industry: Control of Nitrosamine Impurities in Human Drugs), and incorporates a goal in the Prescription Drug User Fee Act (PDUFA VII) commitment letter
- CPG for routine GMP surveillance inspections, 7356.002: incorporates ICH Q9 on quality risk management, as well as ICH Q10 and the ICH Q12 guidelines, nitrosamine RAs and use of alternative inspection tools
Reclassification of medicines
The legal classification of a pack of medicine determines the level of control over its supply. In part, classification rests on how much health professional input is needed to diagnose and treat the conditions for which the medicine might be used. Currently, there are three categories that a medicine can be classified within:
- Prescription-Only Medicine (POM) - has to be prescribed by a doctor or other authorised health professional and it has to be dispensed from a pharmacy or from another specifically licensed place
- Pharmacy (P) - an intermediate level of control, can be bought only from pharmacies and under a pharmacist’s supervision
- General Sales List (GSL) - may be bought from retail stores, such as a newsagent, a supermarket or a vending machine in a shop
The underlying principle for classifying medicines is to maximise timely access to effective medicines while minimising the risk of harm from inappropriate use.
The MHRA has issued guidance for organisations to apply to move their medicine to a different classification.
Investigational drugs
Draft FDA guidance provides information for industry, researchers, physicians, institutional review boards, and patients about the implementation of FDA’s regulations on expanded access to investigational drugs for treatment use under an investigational new drug application (IND).
The document has been put together because the FDA received numerous questions concerning implementation of the regulatory requirements for expanded access.
The draft FDA guidance document is titled “Expanded access to investigational drugs for treatment use: Questions and answers”.
Interpreting the Indian Pharmacopeia
The Indian Pharmacopoeia Commission (IPC) has recently introduced a General Chapter on ‘Uniformity of Dosage Units’ in harmonization with other pharmacopoeias under section 2.5.4. (i) on page 361, Volume I of IP 2022. This chapter is presently introduced in the Indian Pharmacopeia (IP) for information and awareness of the stakeholders and is not referred to in individual monographs and therefore remains a non-mandatory requirement.
Fungi
The World Health Organization (WHO) has compiled its first-ever list of fungal “priority pathogens”. These are the fungal organisms that pose the greatest risk to human health worldwide.
In all, 19 fungi form the priority pathogens list (FPPL). One of the aims is to help to direct global health efforts to research into methods to tackle fungal pathogens, considering that many of the fungi and the diseases they causes represent unmet research and development areas in relation to public health importance.
Many fungal pathogens represent a major threat to public health and several are becoming increasingly common and resistant to treatment. This is in the context of there being only four classes of antifungal medicines commercially available. More concerningly, there are only a few candidates in the clinical pipeline.
The WHO fungal priority pathogens list (WHO FPPL) is the first global effort to systematically prioritize fungal pathogens, considering their unmet research and development (R&D) needs and perceived public health importance.
Medical devices
The MHRA has appointed the first new UK Approved Body to certify medical devices since Brexit. The DEKRA Certification UK Ltd has now joined the three current UK Approved Bodies, increasing the UK’s capacity to process conformity assessments for medical devices to ensure safe and effective devices reach the UK public.
DEKRA has become the first organisation to complete the new designation process that any potential organisation must now go through in order to become approved to certify medical devices in the UK. They are now designated as a UK approved body to undertake assessments for general medical devices (known as Part II designation).
Carcinogenic compounds
ICH guideline S1B(R1) on testing for carcinogenicity of pharmaceuticals has been issued. This provides guidance on approaches for evaluating the carcinogenic potential of pharmaceuticals. It embraces all pharmaceutical agents that need carcinogenicity testing.
Viral safety
A new scientific guideline has been issued by ICH: “ICH Guideline Q5A(R2) on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin.” Biotechnology products include biotherapeutics and certain biological products derived from cell cultures initiated from characterised cell banks of human or animal origin.
This document considers testing and evaluation of the viral safety of biotechnology products derived from characterised cell lines of human or animal origin. It outlines data that should be submitted in the marketing application/registration package.
This document covers products produced from in vitro cell culture using recombinant DNA technologies such as interferons, monoclonal antibodies, and recombinant subunit vaccines. It also covers products derived from hybridoma cells grown in vivo as ascites. The document also applies to certain genetically-engineered viral vectors and viral vector-derived products, which can undergo virus clearance without a negative impact on the product. These products may include viral vectors produced using transient transfection or from a stable cell line, or by infection using a recombinant virus. It also includes viral vector-derived recombinant proteins, for example, baculovirus-expressed Virus-Like Particles (VLPs), protein subunits and nanoparticle-based vaccines and therapeutics. The scope includes Adeno-Associated Virus (AAV) gene therapy vectors that depend on helper viruses such as baculovirus, herpes simplex virus or adenovirus for their production.
Annex 1 webinar series: Dr Tim Sandle has collaborated with RSSL on an insightful series covering key Annex 1 focus areas. To learn more and view the series please click here.