Cleaning Verification / Validation of Pharmaceutical Manufacturing Equipment From a Laboratory Perspective

Adam W. GrobinSouthern California Pharmaceutical Discussion GroupSept. 19, 2013

Disclaimer

Any views or opinions expressed or presented are solely those of the author and do not necessarily represent those of any employer past or present.

TheManufacturingFloor• Macro Scale• Team Activity• Highly Proceduralized• Specific Roles / Compartmentalization

The Laboratory

• Micro / Molecular Scale• Individual Activity• Highly Proceduralized• Roles highly flexible

1. clean▫ a : free from dirt or pollution <changed

to clean clothes><clean solar energy>▫ b : free from contamination or disease <a clean wound>▫ c : free or RELATIVELY FREE from

radioactivity <a clean atomic explosion>2. clean

▫ a : UNADULTERATED, PURE <the clean thrill of one's first flight>▫ b of a precious stone : having no interior flaws visible▫ c : free from growth that hinders tillage <clean farmland>

Good Manufacturing Practices

• cGMPs include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products.

Dietary Supplements / Drugs / Devices

• PART 111--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKAGING, LABELING, OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS§ 111.27(d) You must maintain, clean, and sanitize, as necessary, all equipment, utensils, and any other contact surfaces used to manufacture, package, label, or hold components or dietary supplements

• PART 211 -- CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS§ 211.67 Equipment cleaning and maintenance

• PART 820—QUALITY SYSTEM REGULATION§ 820.70(e) Contamination control. Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.

Seems Simple, so why…

1988, major experience with cross contamination traceable to inadequate cleaning and cleaning validation.

An API supplier of Cholestyramine Resin recall the product, due to contamination with low levels of intermediates and degradants from the production of agricultural pesticides.

This cross-contamination attributed to drums used to recover solvent from agricultural pesticides manufacture at another location. The drums were not properly cleaned leading to agricultural pesticides entering the API manufacturing process.

ROHM & HAAS CHARGED WITH COVERUP PESTICIDES WERE FOUND IN PRODUCTSBy Richard Burke, Inquirer Staff Writer, Philli.com (The Inquirer, Daily News)POSTED: March 23, 1989

It (Warner- Lambert) was one of two pharmaceutical companies using the Rohm & Haas chemical as an ingredient in its anti-cholesterol drug. Introduction of Warner- Lambert's drug was delayed six months last year when the company learned of the contamination

http://articles.philly.com/1989-03-23/business/26126982_1_rohm-haas-bristol-myers-warner-lambert

A recent example…

Europe wide recall of HIV drug due to cleaning related contamination. Reports indicate a MSA storage tank cleaned with ethanol was not free of ethanol prior to charging with MSA.

API produced soon after had elevated levels of a potential GTI (10 x > TTC). Batches made months later exhibited values as high as 2,300ppm (EM’s TTC = 0.6ppm)

ROCHE RECALLS VIRACEPT DUE TO CHEMICAL IMPURITYPatients are requested to contact their doctors to discuss alternative therapies

Media ReleaseBasel, 06. June 2007

Roche, in agreement and cooperation with Health Authorities (EMEA and Swissmedic), recalls in Europe and some other world regions all batches of Viracept powder and tablets. The US, Canada and Japan are not affected by this recall.

Roche has received several reports that some batches of Viracept 250 mg tablets have a strange odour. A detailed chemical analysis of the affected tablets showed they contain higher than normal levels of methane sulfonic acid ethylester. In the interest of patients safety Roche has decided to recall all batches of Viracept tablets and powder.

Patients are requested to contact their doctors to discuss alternative therapies.

http://www.roche.com/media/media_releases/med-cor-2007-06-06b.htm

What does it mean to be clean?

• Modern analytical technology presented a challenge to conventional notions of what is “clean” (a variation of none detected).

• Trace analysis▫ Sports / performance enhance substances▫ Food / pesticide residue, 1996 repeal the 1958

“Delaney Clause”.

Practical Definitions• Cleaning: Removal of residues and contaminants to a

controlled level. The residues and contaminants can be by cross-contamination from previously manufactured products in the equipment or from the cleaning procedure (detergents / sanitizers) or degradation products resulting from the cleaning process itself, as well as microorganism*.

• Cleaning verification: A quality control process for determining the effectiveness of a cleaning process for a specific cleaning event.

• Cleaning validation: A methodology used to assurethe effectiveness and consistency of a cleaning process to remove residues and contaminants

Establishing Scientifically Sound Residue Limits (1993)• No quantity of residue will be visible on the

equipment after cleaning procedures are performed.

• No more than 10 ppm of a product will appear in another product.

• No more than0.001 dose of any product will appear in the maximum daily dose of another product.

Fourman, G., and Mullin, M., “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations,” Pharmaceutical Technology, April 1993

Establishing Scientifically Sound Residue Limits (2012)• PDA Technical Report No. 29, Revised 2012:

Points to Consider for Cleaning Validation

▫ The underlying assumptions are unchanged from basic approach is unchanged from the 1993 Fourman and Mullin publication.

The Approach

• For the purpose of calculation, equipment contamination is assumed to be evenly distributed throughout the equipment surface and any contamination quantified will be considered completely dispersed in the subsequent product.

Practical Considerations

• Assuming a Safety Factor of 0.1% (1/1,000)

• No more than 0.1% of the minimum therapeutic dose of Drug A will be found in the largest daily dose of Drug B

• This is a good start, but how is the limit calculated?

Maximum Allowable Carryover

MAC = Lowest Dose Product A Max Daily Dose Product B----------------------------- X --------------------------Safety Factor Smallest Batch Prod B

Surface Acceptance Limit

MACSAL = ---------------------------- = micrograms/in2

Equipment Surface Area

Swab Acceptance Limit

Swab Acceptance Limit SwAL = SAL X Area Swabbed X Rf

Rf = Recovery Factor (assume 50%)

Test Solution Concentration Limit

SwALSample Conc. Limit = ----------------------------------

Extraction & Dilution Volume

Method LOQ/LOD

• Limit Test vs. Quantitative Assay

• 50% to 150% ?• 80%, 100%, 120% ?

Setting Limits• Product Specific

• Bracketing / Cleaning Matrix▫ Product families: Similar solubility, cleaning

procedure, safety profile. Selecting “worst case”

• Special Consideration:• Allergenic and highly potent materials

▫ e.g. penicillins and cephalosporins▫ e.g. anovulent steroids, potent steroids and

cytotoxic compounds

Microbiology

• Limits for Aseptic Manufacturing equipment can be justified using a similar carry over argument, with recognition that the components of the next product also contribute to the total bioburden

▫ Bioburden NMT 25 cfu per 25 cm2 – This level is readily dealt with by typical SIP processes.

▫ Endotoxin less than 0.25 EU/mL (surface EU x contact surface area = transferred EU)

Useful Assumptions

• Minimum batch size – set to minimum capacity of compounding / mixer for agitation to operate.

• Maximum Dose of Next Product – 4g/day (based on some antibiotics). Phase 1 does escalation protocol

• Equipment surface area – a few pieces will provide the majority of the area

• Safety Factor: 1/1000 by Phase 3, 1/10000 NCEs

Organizational Interdependencies

• The process of developing a suitably sensitive analytical method, validating, and establishing a surface recovery factor is time consuming.▫ Without the required inputs such as equipment

surface area, area to sample swab / rinse, largest daily dose of next product, smallest batch size of next product etc., a residue limit isn’t established. A fit for purpose method is not developed without a target limit / LOQ, LOD in mind.

Multifunctional Endeavor • Toxicology – NOAEL, LD50• Clinical / Med Affairs - Posology• Engineering – Equipment surface area & material of

construction• Manufacturing – Scheduled based on business needs,

execute cleaning, perhaps swabbing• Chemistry – Swab preparation, residue analysis, timely

results• Microbiology – Sampling, bioburden, endotoxin, advise

on cleaning procedures and equipment storage• Validation – Project coordination, protocols• Quality Assurance – Quality system oversight

What Residue to Analyze

• Assuming compendial / GRAS components are used in the formulation, the API is the most likely analyte.- However easily degraded drugs (thermal

instability, air oxidation, easily hydrolyzed, reactive to cleaning agents. - Conduct an exhaustive study of the possibilities?- Establish 1st and 2nd choice cleaning approaches, and

test to those conditions.

Cleaning AgentsA common problem associated with detergent use is its composition. …suppliers will not provide specific composition…. As with product residues, …it is expected …evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process …only added to facilitate cleaning... Thus, they should be easily removable. Otherwise, a different detergent should be selected.

FDA GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES July 1993

• A formulated cleaning agent may contain (in addition to water) a surfactant, an alkalinity source (e.g. KOH), and a chelant▫ It is reasonable to target one component of the

cleaning agent provided there is some rational basis to expect the components will remain in the same ratio, or the selected analyte is an effective reporter for the maximum level of any component.

▫ Using compendial and/or GRAS materials as cleaning agents greatly reduces safety concerns.

Sampling MethodsDirect Surface Sampling Rinsing

• Swabbing• Viewed as more reliable• Insoluble or dried residues

may be removed by physical action

• When accessible, hardest to clean areas can be sampled, indicating a likely maximum level of the residue

• Swab selection• Technique dependent

• Larger surface area may be sampled

• Inaccessible areas can be sampled

• Demonstrating recovery & establishing an acceptable recovery factor

Technical Resource Library from Cole-Parmer

Swab Sampling Technique

Non-Specific MethodsMethodology Considerations

• Conductivity• Total organic carbon (TOC)• Visual• pH

• Short / no development • Typically faster• My be sensitive to other

considerations (excipients, cleaning agents)

• Greater likelihood of false positives

• May require a specific method to investigate OOS

Specific MethodsMethodology Considerations

• Chromatography (LC, GC, IC, TLC)▫ Specific detection modes

(LC-UV, Flour, ELSD, CAD, CLND, MS, MS/MS)

• Atomic Spectroscopy (AA, ICP-OES, ICP-MS)

• ELISA• Ion-mobility

spectrometry (IMS)

• Time consuming to develop• Typically longer analysis

times• Low likelihood of false

positives• Typically insensitive to other

considerations• Cost / training

Time Limits• End of manufacture to start of cleaning ? calendar

days• Start of cleaning to completion of cleaning• Verification sampling• Completion of sampling to initiation of analysis▫ Unextracted vs extracts & storage (stability/recovery)

• Completion of testing to delivery of results of analysis from Labs to X

• Receipt of results of analysis to completion of protocol and submission for post-approval

The Challenges

• Communication, communication, and communication▫ Lack of appreciation for necessary prerequisite

information• Push vs. Pull manufacturing technology transfer• Schedule pressure• Who owns the process

Useful Tools

• Cleaning Validation Master Plan

• RACI Chart (Responsible, Accountable, Consulted, Informed)

• Overview of the process for involved parties

• Clear / executable SOPs

Acknowledgments

• My many colleagues in Pharma manufacturing and R&D

• The work of the PDA Technical Committees and National Regulatory Authorities

Discussion

Setting Cleaning Validation Acceptance Limits for Topical Formulations

M. Ovais, Lai Yeo Lian, Pharmaceutical Technology,Volume 32, Issue 1, Jan. 2, 2008

Single Use Systems