Cleaning Validation Series / Oral Solid Dosage Forms

Cleaning Validation Procedure for Capsules: Hard-Shell and Softgel, Step by Step

A working procedure for validating the cleaning of capsule manufacturing equipment, covering powder-filled hard capsules and liquid-filled softgels, with the limit calculations adapted to capsule counts and fill weights.

⏱ 20 min read 📋 Capsule Filling · Softgel Encapsulation

Labels: Cleaning Validation Capsules

Series note: this post covers hard-shell and softgel capsules. The limit calculations are the same as in the tablets post, with extra equations for turning capsule counts and fill weights into batch size and daily dose, which is where capsule calculations most often go wrong.

In this procedure

1. Purpose and scope
2. Regulatory basis
3. Responsibilities
4. The validation procedure, step by step
5. Capsule equipment and sampling locations
6. The cleaning procedures
7. Worst-case product selection
8. Calculations and equations
9. Interactive calculators
10. Acceptance criteria and hold times
11. Checklist and pitfalls
12. Specimen quality forms
13. References

01Purpose and scope

The purpose of this procedure is to give documented evidence that the approved cleaning procedure removes active residue, cleaning agent and microbial contamination from capsule equipment to levels that are safe for the next product made on it.

Capsules come in two quite different forms, and the procedure has to handle both. Hard-shell capsules are filled with powder, granules or pellets on machines that meter the fill, mostly dosator or dosing-disc machines that form a plug with a tamping pin or finger.¹⁰ Softgels are made by rotary-die encapsulation, where two ribbons of gelatin are sealed around a liquid fill that a positive-displacement pump doses through a wedge into the forming capsule.¹⁰

The scope covers shared product-contact equipment through the whole capsule process: blending or granulation before hard-capsule filling, the capsule filler and its sorting and polishing equipment, and for softgels the gel mass and fill preparation vessels, the encapsulation machine and the drying equipment. This post reuses the framework from the tablets post, so read that one first if the MACO method is new to you.

Cap

Recommended reading

Pharmaceutical Capsules — Fridrun Podczeck & Brian E. Jones (Eds.)

The standard reference on capsule technology from Pharmaceutical Press, covering manufacture of two-piece hard capsules, dry filling, soft capsule technology, and the methods and equipment used in filling, weighing, cleaning and inspecting both hard and soft capsules.

It is the right background for this procedure because the hard-to-clean features of a capsule machine, such as dosators, tamping fingers and encapsulation dies, only make sense once you understand how each machine type forms and fills the capsule.

02Regulatory basis

Document	Body	What it contributes
Guide to Inspections of Validation of Cleaning Processes (1993)	U.S. FDA	Expects a written, scientifically justified cleaning procedure with residue limits and validated methods1
EudraLex Vol. 4, Annex 15 (Qualification and Validation)	European Commission	Sets cleaning validation expectations, with limits based on toxicological evaluation2
EMA guideline on health-based exposure limits and PIC/S PI 046-1	EMA / PIC/S	Defines the permitted daily exposure (PDE) approach for shared facilities2,3
Industry guidance (APIC, IPA)	Industry bodies	Practical worked examples of grouping, worst case selection, MACO and swab limits6,7

The overall sequence is the same as for other solid dosage forms: define the procedure, choose the worst case, calculate limits, clean, sample, test, confirm with three successful runs, and document.¹¹

03Responsibilities

Function	Responsibility
Production	Executes the cleaning procedure as written and records every step, time and parameter
Quality Control	Validates analytical methods, analyzes samples, reports results against limits
Microbiology	Performs bioburden testing where the protocol requires it, particularly for aqueous gel mass equipment
Quality Assurance	Approves the protocol and report, handles deviations, owns the product matrix and revalidation triggers
Toxicology / EHS	Supplies or reviews the PDE for each active
Engineering	Provides drawings and surface areas, including die rolls and pump parts, and confirms qualified status

04The validation procedure, step by step

Work through the ten steps in order. Click each to expand it.

List every product-contact item for each capsule route and group them into trains. A hard-capsule train might be blender → capsule filler → sorter and polisher. A softgel train might be gel mass vessels → fill preparation vessel → encapsulation machine → drying tumbler and trays. Record each item's product-contact surface area in cm² from drawings.

• Include dosing discs, dosators, tamping pins, die rolls, wedges, pump heads, hoses and transfer containers
• Confirm the equipment is qualified before cleaning validation starts

Build a product matrix with dose per capsule, PDE, batch size in capsules, fill weight, and solubility and cleanability of the fill. Group hard-shell and softgel products separately, and powder fills separately from oil or other liquid fills, then rate them to find the worst case (section 07).

• For softgels, record whether the changeover concern is only gelatin or also a liquid drug product⁸
• Reassess the worst case whenever a new product is introduced

Convert capsule counts and fill weights into batch size and the number of daily doses (Equation 1), then calculate MACO by the health-based method and, where policy requires, the dose-based and 10 ppm methods. Use the most stringent, then convert to surface, swab and rinse limits (Equations 2 to 11).

• Use the smallest batch and the largest daily dose of the next product
• Also set limits for cleaning agent and microbial levels

Use swab sampling at risk-assessed, hard-to-clean locations, rinse sampling for large or inaccessible surfaces such as vessels and lines, and visual inspection on everything accessible. Most protocols combine them.⁴

• Define each location, the swab area (commonly 25 cm²) and the number of swabs
• Justify every location in the protocol

Select a specific method such as HPLC, or a non-specific one such as TOC where justified. Validate it with a quantitation limit comfortably below the swab limit. For oil-based softgel fills, make sure the swab and extraction solvent actually dissolve the fill, because a water-based solvent may not recover a lipophilic residue.

• The method must detect residue at the limit with margin
• See the analytical method validation posts earlier in this series

Spike known amounts of the worst-case active onto coupons of each surface material in the train, sample with the defined technique, and measure what comes back (Equation 8). Apply the recovery to later results (Equation 9).

• Test every surface type, including die roll metal, pump parts, tubing and gaskets
• Use replicate spikes, ideally at several levels around the limit

The protocol fixes the products, equipment, cleaning SOPs, limits, locations, methods, hold times and acceptance criteria before any run. Quality approves it before execution.

• Acceptance criteria are never changed after the data is seen
• Define the investigation route for a failure

Manufacture the worst-case product, clean strictly per the SOP, inspect visually, take swab and rinse samples, and test. Repeat until three consecutive runs meet all criteria.¹¹

• Cover the validated dirty and clean hold times
• Record everything contemporaneously

Correct each result for recovery, compare with the limit, and confirm the total carryover across the train is below MACO. The report states the conclusion, any deviations, and the products and equipment now covered.

• Any failure triggers an investigation and a root cause before more runs

Set up periodic verification, trending and revalidation triggers: a new product, a change in equipment or cleaning agent, a change to the procedure, or a failure. A new product re-evaluates the worst case and recalculates affected limits under change control.⁵

• Link to the change control and APQR posts earlier in this series

05Capsule equipment and sampling locations

Hard-shell and softgel lines have very different hard-to-clean areas. Switch tabs to see typical locations, noting that the final list must come from your own risk assessment.

Blending and granulation. Powder fills are usually blended or granulated first, using the same equipment types as tablets: blender discharge valves, corners, mills, and granulator bowls and filters. Use the tablets post for the detailed locations.

Hard capsule filling. Cleaning the fill hopper, dosing plate and tamping pins after each run is central to cross-contamination control on a capsule machine.⁹ Dosator machines add the dosing tubes and pistons, and dosing-disc machines add the disc and tamping fingers, where the powder plug is formed.¹⁰ Include the turret, capsule segments or bushings, and the sorter and polisher.

Softgel gel mass and fill preparation. The gel mass contains gelatin, glycerine, sorbitol and water, so these vessels and lines carry a sticky, protein-based residue and bioburden risk. Fill preparation vessels and the lines to the encapsulation machine carry the liquid drug product and need swab or rinse sampling.⁸

Softgel encapsulation and drying. Gelatin ribbons are cast on a drum, threaded between the wedge and the rotary dies, and the filled capsules are tumbled and dried on trays.¹⁰ Typical locations are the die rolls, wedge, spreader boxes, pump and injection parts, and the tumble dryers and trays. Drug residue can also reach the die rolls and downstream equipment by leakage during or after encapsulation.⁸

CV

Recommended reading

Cleaning Validation: A Practical Approach — Destin A. LeBlanc

A practical guide to the whole cleaning validation workflow, from setting residue limits and choosing sampling methods to running recovery studies and writing the protocol and report.

Because the limit logic is the same across dosage forms, this book is the common reference for the whole series, and it is the best place to look when your capsule situation does not fit the examples neatly.

06The cleaning procedures

Validation tests a written SOP, so the SOP has to be specific enough to repeat. The two capsule types need different procedures.

Hard capsule filler

1. Line clearance. Remove all capsules, powder and in-process material, and tag the equipment with the previous product.
2. Dry cleaning. Remove loose powder by HEPA-filtered vacuum, and avoid compressed air.
3. Disassembly. Strip the hopper, dosing disc or dosators, tamping pins or fingers, capsule segments, and the sorter and polisher parts.
4. Pre-rinse and wash. Rinse to remove gross soil, then wash with the specified detergent at defined concentration, temperature, contact time and mechanical action.
5. Rinse and final rinse. Rinse to the defined endpoint, finish with purified water, and take the rinse sample.
6. Drying and inspection. Dry fully, since moisture matters near gelatin shells, inspect all surfaces under good light, then reassemble and label as clean.

Softgel equipment

The cleaning process can be fully manual or use an ultrasonic tank. It typically involves scraping or brushing, a pre-flush with water to remove loose gelatin, a wash with a mild alkaline detergent, and several water rinses with purified water or WFI.⁸ Within a campaign, the die rolls are often cleaned manually in place by brushing and scraping and then wiping with a clean cloth and water. At changeover the parts are removed and cleaned elsewhere.⁸

For softgels, the primary concern depends on the changeover: if only the gelatin changes, the concern is cleaning gelatin, but if the liquid drug product changes, the concern is cleaning the drug product.⁸ The protocol should state which case each campaign covers and set the matching limit and method.

For all of these, time, action, concentration and temperature should each be defined and controlled, because changing any one changes the result.

07Worst-case product selection

The worst-case previous product is the one hardest to clean and with the lowest residue limit. Rate each product on the factors below, add the ratings, and take the highest total. Worst-case selection is commonly based on risk assessment and rating.⁶

Product	Solubility in cleaning solvent (5 = poor)	Toxicity / PDE (5 = lowest PDE)	Cleanability (5 = hardest)	Lowest batch size ÷ largest daily dose (5 = lowest)	Total
Capsule A (powder fill)	3	5	3	4	15
Capsule B (softgel, oil fill)	5	3	4	4	16
Capsule C (powder fill)	2	2	2	3	9

In this illustration the oil-filled softgel scores highest because a lipophilic residue is poorly soluble in water-based cleaning solutions. Hard-shell and softgel products often cannot share one worst case, so many sites select one for each group. Scoring is a screening tool and needs a written rationale.

08Calculations and equations

Each equation has a worked example using one consistent scenario. Scenario: Product A (previous, worst case) has a PDE of 0.2 mg/day and a lowest standard daily dose of 2 mg. Product B (next) has a minimum batch of 500,000 capsules, a fill weight of 300 mg per capsule, and a maximum daily dose of 4 capsules. The shared product-contact surface area is 25,000 cm².

EQUATION 1

Capsule counts to batch mass and number of daily doses

MBS_B (kg) = N_batch × w / 10⁶   |   n_doses = N_batch / n_day

N_batch = minimum batch size in capsules, w = fill weight per capsule (mg), n_day = maximum capsules per day. Because the MACO formula uses batch size divided by daily dose, working in capsule counts makes the fill weight cancel.

Worked. MBS = 500,000 × 300 / 1,000,000 = 150 kg. n_doses = 500,000 / 4 = 125,000 daily doses per batch. Cross-check in mass: 150,000,000 mg / 1200 mg per day = 125,000.

EQUATION 2

Health-based MACO (PDE method)

MACO_PDE = PDE_A × n_doses

This is the standard PDE_A × MBS_B / MDD_B, rewritten using Equation 1.^4,5

Worked. MACO = 0.2 × 125,000 = 25,000 mg.

EQUATION 3

Dose-based MACO (1/1000 of the lowest dose)

MACO_dose = STD_A × n_doses / SF

STD_A = lowest standard daily dose of the previous product (mg/day), SF = safety factor, traditionally 1000.^4,5

Worked. MACO = 2 × 125,000 / 1000 = 250 mg.

EQUATION 4

10 ppm criterion

MACO_10ppm = 10 mg/kg × MBS_B (kg)

Ten parts per million is ten milligrams of residue per kilogram of the next product.⁴

Worked. MACO = 10 × 150 = 1500 mg.

EQUATION 5

Selecting the limit

MACO = min( MACO_PDE , MACO_dose , MACO_10ppm )

Use the most stringent value your policy allows. Where health-based limits are required, MACO_PDE controls and the others are shown for comparison.^2,3

Worked. The minimum of 25,000, 250 and 1500 mg is 250 mg (dose-based).

EQUATION 6

Surface residue limit

L_surface = MACO × 1000 / SSA

L_surface in µg/cm², MACO in mg, SSA = total shared surface area (cm²).⁵

Worked. 250 × 1000 / 25,000 = 10 µg/cm².

EQUATION 7

Swab limit and extract concentration

L_swab = L_surface × A_swab   |   C_limit = L_swab / V_extract

A_swab = area swabbed (commonly 25 cm²), V_extract = extraction volume (mL).⁵

Worked. L_swab = 10 × 25 = 250 µg per swab. In 20 mL, C_limit = 12.5 µg/mL.

EQUATION 8

Swab recovery

% Recovery = ( amount recovered / amount spiked ) × 100

Determined for each surface material on spiked coupons, using the mean of replicates.

Worked. Spiking 200 µg and recovering 160 µg gives 80%. At the limit the method should therefore read 12.5 × 0.80 = 10.0 µg/mL.

EQUATION 9

Corrected residue from a swab result

Residue (µg/cm²) = ( C_measured × V_extract × 100 / % Recovery ) / A_swab

Compare the result with L_surface from Equation 6.

Worked. A swab reads 3.6 µg/mL. Residue = (3.6 × 20 × 100 / 80) / 25 = 3.6 µg/cm², which is 36% of the 10 µg/cm² limit.

EQUATION 10

Rinse limit

C_rinse (µg/mL) = L_surface × SSA_rinsed / V_rinse

SSA_rinsed = area contacted by the rinse (cm²), V_rinse = total rinse volume (mL).

Worked. 10 × 25,000 / 10,000 = 25 µg/mL for a 10 L rinse.

EQUATION 11

Carryover check in the next product

C_next (ppm) = MACO / MBS_B (kg)   |   Exposure (µg/day) = C_next × daily dose of B (g/day)

Daily dose of B in grams = capsules per day × fill weight / 1000.

Worked. C_next = 250 / 150 = 1.67 ppm. Daily dose = 4 × 300 / 1000 = 1.2 g. Exposure = 1.67 × 1.2 = 2.0 µg/day, which is 1% of the 200 µg/day PDE and equals 1/1000 of the 2 mg standard dose.

EQUATION 12

Equipment train check

Σ ( Residue_i × SSA_i ) ≤ MACO

The total carryover across the whole train must stay below MACO, even if one location has more than average.^6,7

09Interactive calculators

The defaults reproduce the worked example above. Change the inputs to see your own limits.

A. MACO and residue limits interactive

Implements Equations 1 to 7, 10 and 11, with batch size in capsules and fill weight in mg per capsule.

PDE of previous product (mg/day)

Lowest standard daily dose (mg/day)

Safety factor (dose method)

Next product minimum batch (capsules)

Fill weight (mg per capsule)

Max capsules per day

Shared surface area (cm²)

Swab area (cm²)

Extraction volume (mL)

Swab recovery (%)

Rinse volume (mL)

–

Batch size (kg)

–

Daily doses per batch

–

MACO, PDE (mg)

–

MACO, dose (mg)

–

MACO, 10 ppm (mg)

–

Selected MACO (mg)

–

Surface limit (µg/cm²)

–

Limit per swab (µg)

–

Extract limit (µg/mL)

–

Expected reading at recovery (µg/mL)

–

Rinse limit (µg/mL)

–

Carryover in next batch (ppm)

–

Daily exposure at MACO (µg/day)

Enter values to calculate.

B. Recovery and swab result evaluation interactive

Implements Equations 8 and 9. If you enter spiked and recovered amounts, the calculated recovery is used. Otherwise the manual recovery field is used.

Amount spiked (µg, optional)

Amount recovered (µg, optional)

Manual recovery (%)

Measured extract concentration (µg/mL)

Extraction volume (mL)

Swab area (cm²)

Surface limit (µg/cm²)

–

Recovery used (%)

–

Corrected residue (µg/cm²)

–

% of limit

Enter values to evaluate.

These calculators illustrate the arithmetic only. A real protocol uses toxicologist-derived PDEs, qualified surface areas, validated methods, and acceptance criteria approved in advance. Never use a web calculator as the sole basis for releasing equipment.

Tech

Recommended reading

Validated Cleaning Technologies for Pharmaceutical Manufacturing — Destin A. LeBlanc

Explains how cleaning actually works: the roles of detergent chemistry, temperature, contact time and mechanical action, and the features of manual, ultrasonic and automated cleaning systems.

That matters for capsules because a sticky gelatin residue or an oily fill needs a different cleaning approach from a dry powder, and this book helps you design a process capable of meeting the limits calculated above.

10Acceptance criteria and hold times

Parameter	Criterion	Basis
Visual	No visible residue on any accessible surface	Applied to every run and every surface
Active residue (swab)	Corrected residue ≤ Lsurface (Eq. 6, Eq. 9)	Most stringent MACO
Active residue (rinse)	Concentration ≤ Crinse (Eq. 10)	Same MACO, whole-train basis
Train total	Σ residue × area ≤ MACO (Eq. 12)	Confirms overall carryover
Gelatin and cleaning agent	Below the limit set for each, by a justified specific or non-specific method	Relevant for gelatin-only changeovers8
Microbial	Bioburden within the protocol limit where risk warrants	Especially aqueous gel mass equipment6
Reproducibility	Three consecutive successful runs	Standard validation practice11

Hold times. Validate the maximum dirty equipment hold time, because dried gelatin or powder is harder to remove, and the maximum clean equipment hold time, because cleaned equipment can pick up contamination. Each is tested by holding the equipment for the maximum time, then cleaning or sampling as defined.

11Checklist and pitfalls

Readiness checklist

Equipment trains and product-contact surface areas are documented, including dosing parts and die rolls

Hard-shell and softgel products have separate worst-case selections with written rationale

PDEs are available for every active, and MACO uses health-based limits

Capsule counts and fill weights are converted to batch size and daily doses consistently

Swab and extraction solvents are validated for the actual fill, including oils

Recovery is determined for every surface material, and results are corrected for it

Dirty and clean hold times are validated, and revalidation triggers are defined

0 of 7 complete

• Mixing capsule counts and masses. Batch size in capsules, dose in mg and fill weight in mg per capsule are easy to confuse. Work from Equation 1 and state units on every line.
• Forgetting the small metering parts. Tamping pins, dosing discs and dosators sit in the powder path and are easy to miss in an equipment list.
• Using a water-based swab solvent for an oil fill. A low recovery may then reflect the solvent rather than the cleaning, so validate the solvent first.
• Ignoring leakage residue. A leaking softgel can leave drug product on die rolls and downstream equipment, so include those surfaces in the plan.⁸

Worth remembering: for capsules the conversion step comes first. If batch size and daily dose are not stated in the same unit, every limit downstream of them, from MACO to the swab result, will be wrong in a consistent and convincing-looking way.

12Specimen quality forms

A protocol summary and a sampling and results record, ready to adapt to your own procedure.

Form CVC-01 — Cleaning Validation Protocol Summary (Capsules)

Specimen only — not a controlled document.

Protocol no. / version

Capsule type (hard-shell / softgel) and train

Worst-case previous product (PDE, STD)

Next product (batch in capsules, fill weight, capsules/day)

Item	Value	Calculation reference
Batch size (kg) and daily doses per batch		Eq. 1
MACO (PDE / dose / 10 ppm) and selected		Eq. 2 to 5
Shared surface area (cm²)		Engineering drawings
Surface limit (µg/cm²)		Eq. 6
Swab limit (µg) and extract limit (µg/mL)		Eq. 7
Rinse limit (µg/mL)		Eq. 10
Dirty / clean hold times		Protocol

Prepared by / date

Reviewed by (QC) / date

Approved by (QA) / date

Form CVC-02 — Sampling and Results Record

Specimen only — one row per sampled location, per run.

Run no. (1, 2, 3)

Date / cleaned by

Location	Surface material	Method	Measured (µg/mL)	Recovery %	Residue (µg/cm²)	Pass / Fail

Visual inspection result

Train total check (Eq. 12)

These specimen forms illustrate typical content only. Your quality system's document control procedure takes precedence over this format.

AV

Recommended reading

Handbook of Analytical Validation — Michael E. Swartz & Ira S. Krull

A handbook on validating the analytical methods behind cleaning validation, including specificity, accuracy, precision and the detection and quantitation limits needed to measure trace residue.

It supports step 5 of the procedure: the swab limit from Equation 7 is only meaningful if the method can measure it, including in an oil-based or gelatin-containing sample matrix.

13References

1. U.S. Food and Drug Administration. Guide to Inspections of Validation of Cleaning Processes. July 1993. fda.gov
2. gmp-compliance.org. "Shared and Dedicated Facilities: EMA Publishes Final Guideline on Setting Health Based Exposure Limits (PDEs)." gmp-compliance.org
3. Pharmaceutical Inspection Co-operation Scheme. Guideline on Setting Health Based Exposure Limits … in Shared Facilities, PI 046-1. picscheme.org
4. CASRAI. "Cleaning Validation: Worst-Case Grouping, MACO, and Acceptance Limits." casrai.org
5. Leucine. "MACO Calculation in Cleaning Validation: A Complete Guide." leucine.ai
6. Indian Pharmaceutical Alliance, Sub-Group 4. "Cleaning Methodology and Validation Best Practices Document." ipa-india.org
7. APIC. "Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants." 2021. apic.cefic.org
8. Cleaning Validation Simplified. "Dealing with Liquid Gel Capsule Filling Equipment." cleaningvalidation.com
9. JinLu Packing. "Pharmaceutical Cleaning Validation: A Complete Guide to GMP Compliance, Protocols and Sampling Methods." jinlupacking.com
10. Pharma Excipients. "Capsules Production: Microcapsules, Hard and Soft Gelatin Capsules" (chapter). pharmaexcipients.com
11. PharmaGMP Guide. "Cleaning Validation in Pharma: 10 Proven Steps, Complete SOP, MACO Calculation Guide." pharmagmpguide.com

Disclosure: This article contains Amazon affiliate links. As an Amazon Associate, this site may earn from qualifying purchases at no extra cost to you. Recommendations are specific to cleaning validation, capsule technology and analytical validation and are not a substitute for your organization's own quality and regulatory guidance.

This content is for general professional education and does not constitute regulatory or legal advice. The procedure, equations and example values are illustrative and must be adapted, justified and approved within your own quality system. Limits must be based on toxicologist-derived health-based exposure data where required.

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