Keeping the flies out of the ointment

1. Keeping the flies out of the ointment What else the NHS Supplier or Manufacturer needs to think about Stephen Langford Pharmacy Production Director Calderdale & Huddersfield NHS Foundation Trust

2. This presentation covers • The costs of small volume niche manufacturing • On-going investment in manufacturing facilities • Breakdown of systems costs • API supplies • Product development • Background • Issues • Resilience and reliability • Resilience through collaboration • Case studies • Key messages • Collaboration to NHS benefit?

3. The costs of small volume niche manufacturing • Historically most NHS PMUs have and still operate at the margin of profitability; if at all. • Now being asked to operate as self financing units; • Covering operating costs • Return investment costs to the host Trust through SLR. • Cover future investment requirements. • Deliver high service level (delivery in full on time DIFOT) • Meet full regulatory GMP expectations • Development costs for new products • This is presenting several challenges

4. On-going Investment in manufacturing facilities • In 2003/4 the NHS invested £46 millions in the NHS PMU network. This does not include commissioning costs and subsequent project corrections (£60 million is a realistic investment cost over 10 years). • A new –build regional level PMU involves an investment of £10 to £20million • As a consequence: • A regional level PMU with 50 staff providing sterile & non-sterile manufacturing (without internal aseptic dispensing operation) requires a turnover in the region of £4 million + p.a. for financial viability against a transparent trading account and to generate sufficient funds for future investment. • An ongoing annual investment of £ 100,000 - 200,000 is required to maintain and update equipment/plant systems

5. Breakdown of systems costs • Sterilizers; WFI Stills; gassing isolators weigh in at £150,000 each. • Most “small “ manufacturing systems (bench top ampoule fillers; bottle washers) at £50,000 • Filling and capping equipment between £5,000 to £20,000. • Business Management System - £15,000 p.a. • An industrial scale system e.g. ointments/IV bag filling system approx £250,000 • Annual maintenance costs are in the region of £3- 400,000.

6. Active Pharmaceutical Ingredients (Raw materials) • International supply chain with major quality issues. • Minimum of six months to arrive e.g. noradrenaline; dithranol; adrenaline; cocaine hydrochloride. • NHS QC staff are putting in massive efforts to source, validate and test API supplies but do not have the resources to visit plants in India & China. • European sources (if available) considerably more expensive e.g. dithranol 60p per g c.f. £3.50 per g • Considerable outlay in up front costs: • Noradrenaline acid tartrate £20,000 per Kg • Alfentanil £26,000 per Kg • Adrenaline acid tartrate £35,000 per Kg • Crude coal tar £55 per litre

7. Product development - background • Stability data – only some large PMUs have the resources to fund (minimum start up cost £5,000) competent studies and there is still a large legacy of inadequate or minimal data. • Information & Data has value – intellectual property • Stability of some products will have to be based historic custom & practice e.g. coal tar preparations. The value of the “business” is never going to generate the required funds. • Stability has to be assessed in real time. • For the batch manufacture and distribution there is no point in producing a product with less than a 6 month shelf life.

8. Product development –the issues • All product development is done at risk and costs incurred by PMUs. • No commitment to purchase products even when specified in Tenders e.g. • Alfentanil 25mg in 50ml vials • Oxycodone 10mg in 50ml vials • Even when tenders are won; refusal to purchase at the tender price; • Fentanyl 50micrograms in 50ml vials • Inclusion of single user and “wish list” products. • Aseptic service tenders have seen the proliferation of “89 day” products to evade end product testing. • Unreal expectations of development timelines.

9. Resilience and Reliability • Out of a total 1500 NHS product lines; 376 sterile product lines from single source PMU of which over 100 are clinically critical • Above includes 108 ophthalmic preparations. • Resilience works at several levels; • Are there backup plant systems e.g. compressors and sterilizers? • Early warning systems of impending trouble. • Have critical products & processes been identified and contingencies put in place? • Robust stock control & demand management requires co-operation from customers (including clinical specialists) • Over-production – allow for wastage in product pricing • Alternative suppliers for APIs

10. Resilience through collaboration • Not straight forward; • Need to retain customer base in competitive market. • Redirecting customers – inconvenient for all concerned • Buy in stocks for onward distribution – requires Wholesale Dealers Licence. • Set up potential alternative manufacturer requires; • When to activate – manufacturing from scratch requires some weeks lead in (especially sterile products). • Batch Manufacturing Records • API available (or transferred from source PMU) • Slot into existing production plan. • Agreed equivalent specifications; presentations, labelling given different plant & equipment systems.

11. Case study 1 • Failure of double batch of Cardioplegia solution. Out of Specification breakdown product levels due to alterations in pH. Clinically not important. – but customers refused product and cancelled theatre sessions instead. • Unique API (Procaine hydrochloride – no other NHS special uses it) • Total NATIONAL demand each of A & B is 2000 units p.a. • Multiple site manufacture untenable; the product has to generate a worthwhile return. • Financial return on product OK but not spectacular • Now over-producing to guarantee 100% availability & price increase.

12. Case study 2 • Noradrenaline injection • Intervention following withdrawal at no notice of major PFS supplier • Intervention with support from the CMU. • Approach to manufacture terminally sterilized bulk solution to support PFS. • Supply situation with API . • Lesson – no visibility of pre-existing stocks • Industry has picked up – six months later. • Note bulk terminally sterilized solutions add safety to aseptic processes & cost effective. • Now supplying both NHS & Private provider

13. Case study 3 • Povidone iodine ophthalmic solution • Approached by major NHS user; • Existing products very expensive • Supply issues due to complex aseptic manufacturing method. • Less than ideal presentation for theatre use. • Agreed that only a terminally sterilized product could be manufactured in “volume “ to address supply & cost issues. • Ideal formulation: • Povidone iodine in BSS + Heat = No iodine. • Reformulate

14. Case study 3 cont. • Sterilizable screw cap container system of appropriate volume – two pilot batch integrity testing failures before getting right container/closure combination. • Real time stability study • Six months in development + stability testing. • Negotiated price with customer considering their budgetary limitations • While this is a considerable success – development costs were carried by the PMU.

15. Key messages • Unlicensed medicine manufacturing is diverse and complex supplying a niche market. • Sterile manufacturing facilities are particularly expensive to build, maintain and operate. • While there is abundant non-sterile NHS & non-NHS capacity; non-NHS specials supply to primary care has opaque manufacturing and trading practices. • Private sector prices are 150% to 1000% more expensive than equivalent NHS PMU products. • However NHS prices have been historically underpriced and from the above cannot continue given that PMUs must now prove financial viability.

16. Collaboration to NHS benefit? • NHS Pharmacy Procurement and Clinical Specialists need to engage with PMUs – they are part of the NHS. • Suppliers of last resort: • Oseltamivir oral solution • 4 interventions by Huds PMU alone over last two years in response to critical product supply issues. • Active participation in product rationalisation and development by PMUs; Ophthalmic & ULM Working parties (Paediatrics; TB Medicines & Dermatology products) – support of QUIPP. • Collaborations with Industry are happening – but you need to know who you are dealing with and what is really on offer. • Inappropriate tendering will be destabilising; the uncontrolled exit of further NHS manufacturing capacity as a result of tendering will have consequences for patient care.